MOLECULAR BASISOF DIFFERENT LEVELS OFAUDITORY DYSFUNCTION

ATEEQ-UL-JALEEL

Cf,NTRE OF EXCELLENCE IN MOLECULAR BIOLOGYUNIVERSITY OF THE PUNJAB

LAHORE, PAKISTAN(2009)

MOLECULAR BASISOF DIFFERENT LEVELS OFAUDITORY DYSFUNCTION

A THESIS SUBMITIED TO

UNIVERSITY OF TIIf, PUNJAB

IN IUIFILLMENT OF TUE REQUIREMENTS

FOR TI{E DECREE OF

DOCTOR OF PHIII)SOPHY

MOLECULAR BIOLOGY

ATf,f,GUI,JALf,f,L

SUPERVISIOR

DR SIIAIIEEN N. KHAN

NATNNAL CXI\ITRE Of fXCELLENCE IN MOI-ECULAT BIOIOGYUNIVERSTTY OF TIIE PUNJAB

LAFORq PAXISTAN(2txDl

IIIE NAME OF

ALLAH

THE GRACIOUS

TIIE MERCIFT'L

DEDICATED IIO

MYGREATFATHER

wHo coutD Nor uvE roNG ENouclllo sEE Hts WtsHES COmE nUE

IHTOUGH IH|S WOiK

TOMYMOTHER

WHO IIAS I.EFI NO SIOI{EUNIURNED

TO SEE IIE GTEAI AND PNOSPEROUS

ACKNOWLEDGEMENTS

Tb&ks 10 Almighty Alhh htb bldsed m€ witn a[ ihe wisdom, @nviclioi.

.c5,, pordrirl ud d.tuiie dnldiE lo or oc $b l€diG i3* dsigrEd ro rc

t .n higt'ly if,d.bled ro Prof. Dr. Pj@lddin Sheiktr Di.€clor, CEMB. Uniw6ity

of $e Pujlb, fd hi tind Eanrrr .'d h.tlitt

I dprc$ ny d@pes th&t! to my srthy suF*isr ProfeMr Dr Sl[nq N.

Kraa for hd .egula. *noLrly. ilhEiri@e &lvic., k6 iir6E! @pd.tid &d

domging attitud. which h.! bm a @l $ure of icpir.tio. for tu dding this

I m spqtally indebt.d to ny Mtor Sbnid Yd Kh!. for hs @6hir8 &d

dpgDrioi I m ds rh6r$l to dl ny rcspeied hior for th€ir 8!id&E ald

I .l$ wish rc dpB my th&tu to dl ny @ll..s!s od friods for tno. 8..'d

@npdry, tire devotio[ syerSi.tic bdt, @{pdatim !d eppon duing ny l!3wcn

FiMly I &lms,l.ds. rhe $ppon, @{pdition ..d .l1@6gEnd'l de.d.d ro

m by ny wife by shaing with ne dry ap61 of ny m* and givils valurble

ATEEq'UL''A|-EEL

CERTIFICATE

X is cdi6.d tl!! th. t@rch Mrk deiM in rhir tr6is b rh. odgirEl M.t of dE

.utlq At €C-Ul-Jdel .!d ha bd @i€d our !.d6 6y di61 $pdvirion. I hlve

pceElly s@. t!.ood a[ dte drt r€9dl.d in th. mesjpt ed 6fry lhor

@Eldrsvdridnidty lt is furlrq qtified th|r lb. nltsid incrud.d in 6b tnatu ha

rcr b€ u!€d in pan or tuI in a dmsipt dddy sbniftd o. i. lhe prl)c* of

$boiriid in p.nirt@spiac tutflD@t of t .Ed of .ry oils d"g* fr* !ryothq irltituton. It is dso enificd thl Ue rhdi! ha bd prcp!red lndq my sp€flkion

t@rdi.s b tb p@ib.d fdnx .!d t qdoF b cv.lutds fd 0E dttd of Ph.D.

d€E throush th€ o6.i.l prd€duG ofth€ Univesg.

In a@d.re with dE tul* of the Canre dli| b@k! * 5?8 dd ?36 e decl&.d

oMp6d.bL doorn d fid {ill b. t pt in dF tlritty oftlE Cdm! fd t niiinunitu6 rq3 ftom rh. dal. of tn. dBis defee ddin liotr

SigEn]c oftu Supdisor:

N!ne: Dr. Shnhcc!

( Ia \u- ,.t ttta-N. Khd

TAELE OF CONTf,NTS

LislofFi8ue. ... .. ........... I

LirofTo!€.... .... ........... . .... 1

Abtrevi.rid rd Sy!$o!........................ ....--...................... ..... .lvSuon rur... .. .- -. ...VI

rrrEddir...... .. ........................ .... .la\4r!rr:Rqi*oirheLi1ari6............................... ..,.... ...............5

sa.tdJ: Th.Er Andony ardPhysioloe/......... . ... ......... ........ 6

l.l. Arlrorltofl|l€HmE . .......-........ . .--... 7

Lr.L Orq Er............. ................. ... ............ 7

Ll.l.lPiM ........ ........... ......... ..... , .. ..7

Ll.f2EJdsElArdiloryMd6.............-- .-- 7

Ll l.3Tyr'pad. Mdhe............ ..... .... .7

Ll2MiddLE!........ ... ............. ................ ..... 8

l.l.2,l Audbryod:16...... . . .. ... 3

l.l.3.fffiE$..... ........... .... 9

l.l.3.t Osas lltldhlh. .............. . ... . ..9t. |.r.2 M.6ltDB rlbarlh

1.14 Orsuofconi .. ......... ..... ..... .... .12

Ll.4ll{ircdlt. .. .. . 13

Ll,t2 SlD.ili.lirb,.. ... .. . . 13

1.2 nrlsioloe/oftheH|||nEr' I5

l.2.l. SoEd@rnr.rb.pdi*6v.. .. ---....-- .15

I2.2 Mdt{Mlod dLlBdulbn ..... . .... 16

l.2l F!qE!qd!dbdi6.loo8S.tdilr@'!L@ " 16

lir.r,a-, ardiro.y drlndrin c|lsiEelih sn mb.ult bdG .... l3

I3 Clssitcdidofeldjioly 44n41ion .... ... ,...... .... 19

1.4 Clsoalnidy dFtdi[ . ... .... .. " 20

1.4.1 ENirc.lEtti @8, 20

L4.2 Ga6c@........,,,. .. .... . .......... .. 2)

1 .5 lrv.b of&ditory dysfurcrion. ....... ....... . . 20

r.6 srldtorsolaic h6i oa&niroryq^ntciq............... ... 2lI 7 Inhedia@ old*68 lnn..... .......... .. .......21

l7l NdsylrdMi Alo$nit R6iv. DatBs ............... 22

s?.rm-3 Mrpping dilde sa6 b Link!€! tu.b.is .. ..... 25

1.3 Lint!a.AElrsis....... _......... X,l3l. RMnbin tion6&lio. .... ..... 27

I 3 2 The LOD S6a md.d ... .... . 27

133 Munipoint M?9phg .... ..... ..,., .. ..... 2s

13.4 DNA PolymlllBm s ! iool for linlage !E&t . ..........23

Crrp.r 2 t teirls trd Mdlbds .. .. ... ..... 29

2.1 Fiddwo*..... . r02 Ll rddtifdionof h.ling a|Ie1d f.niti6 ...... ...... ..........302r 2. Enh[tHt ofid-tif€d tsiti6 !d ol€dion otb]ood

supt6.... ..... .... ......... ...302 t clinicd oduai@. ........

221. AudiolorirtTeshs ...... . .... ....... .. ...... 3l2.21 I Audiontry.. .. ..... .'2.21 2.Tytrp@nsry ..............- .............. ............ ...r1

222. Ve$ihdardng ..... ......... .... 34

2 2.2 l. &or$qB 16l ....

2.2.22 Ted@C!nl61. ...... ....... ...342 2r. Ctnirt trKd o dinni! ugGl@ . ... . ... 14

2 2 3 r. FunMpy or opl hdtueoDy .. ...

22.3 2 Etc.ftrsiDs'uT.s (EiC)... ...... ...... 3523lilodoryWo& .. ....

23 L DNAEI|r.di@dohttL.dsrqt6-. ............ .. ..... 15

232 QMlift.lion otDNA23 2l. onid d6iq n6rl!||!s (sp.elptdon qy)... 36

2.3.2.2 As{oscet denotb,en 6ddio....... .... ... 16

23 23. Wortir€ DNA dn,rj(s ........ ....... ..... 3?

2 3 3. Prlpd.lion ofGhr dd cplis DNA phr6.. ..... 17

2.3 a L!'||ec arbsi! ro. r4bned bFrndrdic tcsircd*h* t@i.. ........ . - ,... . ....... ...... ... ... 37

z3.4.l. Anplificado ormi@sddtit nEi€Eb pCR.. 37

23.4 a PCR cycL.... .........332.3 5. CoDGWide So ..42

2 3 5.L stlrdddidi,n of^Br pRtS#Li &. Mlppos Sa

MDl0 44

2.3.5.2 Mrlriptq PCR pol@t....... .... . .... ........... 48

23.5.3 Po€trdlirlqpcRcyck 48

2.36Pcpdllirnof$rDk ro.CaaicAdyF ..................

23 7 AuiozErel l|rclMr B-orypDS.- - ........ ...... ........4s2.3.3. tkplorye Ardysij ................. 5l2.39 Dalaoigetiio. dd db\36 6i.s Mlds ... ... .. .5t

al.9 L Ddlsi.d ...... ...51

2.3 9.2, Rdga SEa ...... ............. .... .................... ...5l2.3.9.3 M&o ot6.rbnd @'lfu&.... ...... ... ....... jl2.3 9.4 t\{odulG.

2.r t0 LODs6cC.lcut.rin .. ........... ................... ....5123.t0 | LODS@rhlroulpur. .... ........ .... .. ..54

2.3 r l DNA S6qmg for m,tdion l arulyli! ...... ..... .... . 54

2.l.llIEMuptif.ajd............. ...........,........... ...5423.ll2.EXGSApTran@r.... .... ......

2.l.ll3 S€qEiog Pjjn .. .... .. ..... ......... ....552 r l I .1. Prepei4 a pod'd ror !.ql&nte o cnEtjc ArE a....5523. r 1.5 AolsirofDN^S.qm ....56

C/,rp.e.,3 Rculrs rnd Ds4si@,gddJ: tiilrge An tan f6 Rltoned Aui@rrt Ra6irc

D€olbe$ (rFnE) bci ....

PDlo€E.... ...

Linlage lo Dr' B;Li ,4.roDFNa4p6 ..... .....Ln*\z. ro DFNAT/l L.....

Litr'ae$ DWD294:LDN l1 .

5r4'm-2: Mappiis of rhe N4 adoso4! R4sive Non-srn&omcDa66 LatrnDrt A/.rClrmrl9Pt33 ..... 70

Bckroud ......... ..... ..... 7,

Lr R@nin8ofDFJvtT2: Afoeln ht DFNS3|........................ . 72

PKDF335,..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . :. . . . . . . . . 72

Cfiri6l ddtdin. _.. .,...................72

tudbntricF!6h.....................,........ ____...................... T)

HadoqF rr$sir ofPKDFJ!5 nd Urt,g.6 MNan,,....._........12

&6Emntof PKDF:|35 lint.gcboDdri6!odonFDr)v,dr.... .?3

Akr. ftqEq' 6fof:lio6......... . ........................,,,,..... .........j3

TFpoirtL,OOlscdordiN..............___................................73

32 r@?ig ofia&'f!': lEa DFNBaI __.........__.-......--.... jaPKDFl04t........................................................,,.... ..............?3

c1ini61d.1udion................ .. .... ......... ....,.... .... ..?3Aldiondric a.lurrim ........... ............................... ..............n

Li*.a. tCtli! ofPKDrloaa -d 4dls ofB bo! DFtvrBl 7i3.3 R.i.6E!r ofDrt872 houdtia..... ........................ .. .83

PKDFll04............... .....,................33

Cjiric.IHttory. ......... ....... ...................,,,,,...,.... ..........33

Lirrrg. .rutrii ofPKDFt 104 .. . ............. ............................. ajR!6rGdDtM22 borLn ....................._____.................... ..........86

3ac'qriBofcdihes!E.,........................._........,.,,,,..............3a

&ctd-3: Dision ............. ......... .93

Clipql R.fqa.e.......... ___.......... ............ ............. ...........td1Elcdror'ic innd! irforMioo... .......................I3Pabndifu -................. ........... ............ .......................................... l 14

I

LIST OF FIGURES

llRdti8.......... ....... . - .--. ... 35

'nm.ycltrE prolil6 of PCR prla,m .. .. ...

chm@e@*i* *16!ric E rsu&o ofib. AEI PRISM!

Link8. mpping * MD|oulHD5........... .44'IrE Dcydie pbfi. for &di6olim ofPld dl6 in

frJtiDlsBcR. {A

2.7. A lTfof ElehprEoeM ..... . .. ... ......tn2 3 troedE b m rl, l1ts5 @.x6t goq?. dd! ..... .. ........... .52

29 nldmqclina podl€ fors.qlen8eio... .......... .... .56

3l Pedgednwr€ of&nily PKDFI46... ...... ........ .... or

3 2 Audroerm oaPKDFl46 ...62

3.3.11C26,t, clmmr.gr4 .......62

3.4 /'edt odolosB ... ....... ..... ...... .....62

35.PdigerLr*in8of6nilyPKDF333.... ......... .................... d3 6 Aniogm of PKDF333... .... ... .. ... ........................653.7. Pedige dawing ofhnit PKDFT 107. . .... ............ ......... . 63.4 Ardiog|m ofPKDFl lo7

3.9.redt@&tuinsofftribPKDF488............................ o3 I0 Au{tiqmofPKDF4a . ... ..... ...... .............. 6a

3rr a7,D.t'r./,drmn{og'a.. ......... ...

3.r2.Cladt*uqtt]l,g6.............................................................69

3. It P.diSEd.rinc of nlit PKD8|35........--............--.........-......... 75

3.14 AullrG ofP|(DFJ35....,.......---.........-----............-.....-.-...........?5

3.l5. P.digF &e!8 ofn itPXDr1048..............----...........--..........80

3,16 Aulog|e of}XDF|043.......................................................,..,,3I

3.1?.P.dlg6||IlritrgoftuilyPI(DF|1O1,,,,.....,,,,.......,,,,.....,.,,.....84

3.18 AudiogmolPKDFll04,,,,,.... ...,,,,,.................... ..........,,,,.....8t

3.|t. Sdo.li @4qds othrrg. '!8im

ofputlil'.d &d EEn d

Dmt72 dr}.w l@ DFNtai...,............ ..........................at

3.r. CoE.iqed in rt6DFrrBS, [ {.i -vn.........................,.093.2f. G-- .q!rd n dE 6dn d DEND2 irtCt i,'an.----..........9

tn

LIST OF TAALf,S

Ntt,bn PdstL L l,ci fq N@{tndoni. Au@ml R4!iw D.!68.............. ..22

2. L Crlo&rls fc ilE @r6rir of C.Dtric DNA ...... .......... . ..36

2.2. Miros.rdliL @,ts 6cd for [nl4e.Db6ir ofr.pon.d ]oci,

wilh droostr lpditio(incM)............. ...,.... .,,,. .........39

2.1 Rdin dn@ for PCl'.... ........ ..332.4Sut.Lrdiz6dldrofrdiplqPCRol@hpdd.. .......45

2.5. &dih nirtwforqUf cii!orPCR F.t81s.....................54

2.6.Radbrai.\r@lorE)(GSAPTT.&Ert ...... .......... .....55

2 7. n!.ciD trixrw for 3eqqcidg l{iid............ . .................... ...55

3.1. T*poir LOD s6 b.ctt@ 19 hlcd dl* ir tuitPKDF335..... ....... ......... ......... 11

3.2. TeFFhr LOD s6 for .h|ffim 19 116 in fuilyPI(DFIO{a.,. ............. .. ........ ..... ..............................82

3.3. Ttu.Doin LOD s6 for cl@nN@ 19 nEl6 in &ritPKDFII04... ............... .... ................................. 36

3.4 kinh wd for !.qENii8 of ?!'PIS'9 d6............ . .... .91

35 kidts 6.d fd !.q€d.g of tiN M..................... ......_.q2

3.6 Nat d6ign .t Di.ro6.rdtib wt86tt€6,turof DFN,72..92

ABBREVIATIONS & SYMBOLS

A Art rb. nil MueAT?^de6i&T'Phos|ulcbp BcP.n m Mill'Mc CIGiB nM Milin le

cl cNddciocM Cdri-NiorCs NaCl sodiM Crnoi.tr

Ci ColfuitrNsr|L Nd.yn rerc gding la

d.r D.ldiu Nelcdid.DFN D6ft6 X-rddtDFNADsn6.An@ndb|lld OHC!olrdH,irc.tkDFND r* Ad@cr R6irc oMtM onli4 n ndclio tlhail.& in MrnDNA Dalrihofloloiceid p tdgmof Cnsnl,lGdNrP Dor}lEldd.Tn-Pn qiic pcn potrn6cbtundidEDra Eln9or.diuimrel]@b -FAMj{jho5Frc.

q Shdmorchl]l|@3 cndt m Rdi! nPisl@@HEX ,r.7,2 ,,r

"5 .7:lkx,.htoft{- RrE RdietpjsndE rri€ru

dno.yal@in Di REvddicFMj@HL Hainrrd sDS s.djm Do&al Sdrare

Hld l{ord (in Fm qd.) :ril- s}dMjc }r€rjns 16bf. HM r fty,idt

,T E. Tn+EDTA

14 ft.m.qllmrd T@h Dom

K.Pda-uioKb Kiloboe €,bo(}durcjnKCr Pfujnchldi& fir Tdinn@&g/4(dmiJKcl PoBimct rjih Tfr MetinAT.rnDedDeLOD Ltcrihood ofod& Trp Telpd@(inpcRqd.)M Mor. rxE T,b-N,ct€DTAr'rb Megab& rds FietDdrdynErhit miodhmMacrr rr4Gju chbfi& usH usr.rsrdm

USI|IE rrbqd@lD. rB

S t.dddF da

c Coqdelrittr.!.

- lla.oqtu r&i.a!

E M.L

x a'!dd.d.!.iou!.cd &.ld & CUr co.&ctd)

' $nid-dbr4qtrrdaddlogu (Bo. edldd)

o ltllddsn dr!.to-d!Gt!d;d!d(rir

t6c Uiiidtdsii. socd.tLrs Ti.dDlob nrbdi

riCBI rSol C-abHacbLd

SUMMARY

Au&ory dlEnDdion ir oE of the @t on]lm @roeery defdr6 h hulleln the P.kisla.i popuklion $is trait is obsd.d at a td. of I 6 pd l0o0 individuals, and

h.tr of rh. clg &. hsir6bl. (ELti ,, or., 193) TlE P.lisr4i popularion is a good

eu@ ior gs.lic sudi€s of deiEs s ddoNtra€d by lhc fa.l thd it ha altady

@.r.ibur.d to th€ idsnificaiion of 25 hcrtdiury datEs loci, ed in ih. idorifiqtion of

16 oalh. ols.tircgprc! !r th€e lci. whn it ir ecidt€d dtr a.ol!l of-loo 8e6 rcrcquir.d fo. nomrt tuncliming of thc tmndm d Ori.dlm rd Ctiffrth, 2003),

oilt ll8 d.anB ldi h!rc be. laelt d io d!re, !d tt @sliirc g@ !r onlv 49 leihav€ bd idoti6.d so f& (Hcrcdi&y hesng Io$ hoo@.9€r

l pJ r.bhol u &.b./hin) Thrt FMrr ! ncd fo. mrc llgch in this freld ro unlet

th. s@.e$ ofn|nM aldiiory phFiology ed dofttds

D€ 6ior obj*tive or thi. sardy 6lo idaniry the nololJ ba! or edno'v

d'5irclion *p!6r€d |t diltddl imp&mdt lercls (nild mod€rate, s*r€ or

pofound) by u$ of lh. Ssclic dstst t-hniqE kioM 3 liiltge .Mlvsis (M.4li a'

dl, 2OO3: Peiii .r rr. 2OOl). 1o rhide rh! objedive fiv 6nili6 with @ng@it l

dc.fn€s sgre8.iing i. & tutosnd tuBsive node of inhcriioe w@ iddfinen, dd

hlood eDpl6 w@ @[.ded. DNA B qth(*cd frd blood sd6 od lir'log'

Mdye! w6 p€rfomed on 25 $leled fimili.s to sr.h fo. linlag. to th€ previolslv

r€rDn€d Jno$n l cenve deafB loo 0ldldiLry HdinA t]N Hon p.gel

htror/w.bho1.u!&bs/hhh). Fou famili€s snowed liills. to DFtBllPDs, D|NB7,I

&d DI.NB291('LDN!4. S.q!.re ltbsb of two linlcd fsils @hed in

iddonqdor otoe eDon.d ruilrion (c?l6DA p.V239D) it SaC26A4 (DFNDI) ad

oft nov.l mr.tio, (c 23 r c>Ti p.A94v t i CLDNI a <D|NB'9) seM.

A gtuDFwide tu ws ps,bt4d oi tm sdcd€d udiik.d &n i6lo s.ch

fot rcvel loci itvolwd in &ditory dFtundion The e6one !q ofrh. f@ilv PKDF335

h.lp€d in th€ disve.y of ! na l€6{ve d.!ft.s !ms, Dlxr2?, al chrcmoe@

l9Dl3.l-13 2 *ith a dili..l linl,s€ itl.nd of0 74 .M berlN@ ln. rukd Dl9S2l6

(20 or cM) od DI9SIOI4 (20 75 .M) (N^ et al , 2007) tild ot! rcfilmml of

,FIVA72 ws oni.d oul *ilh lhe lldp ol nqly defrn d Mtd .nd two ture fN,nili6

vtl

(PKDFI048 dd PKDFI104) liil.d to the chrc@o'Ml r€gioi dc6'€d by lhe p@ious

DFND?2 tanili.s. Tn€ Gf.d€rtt indic.rcd thll ohrcdo$mc l9ol33-132 was a

h€rdog€|d3 l@!, nrtoring tm ditrqq d..fB lo.i @ tlE Fon'sl 6d di*d

6ds of the raioust r€po.ted cdtlc€l linlcgc intdtl. Thb @lt.d in rcdnoer orrhe

Dalvnz2 l@s to th. trncdlt b.rwd rhe nart@ D19S1034 (20 75 cM) trd Dl9S39l

(2a.83 cM) lDmins 8.08 cM. Sirulr,t@dy. . mv.l l@s Dlrvral (a dei8t ed bv

th€ HuGo nondd.rurc @min*) @ tupp€d bei$@ Dl9s8?8 (6 57 cM) ed

Dl9S895 (l8.l5cM), d@n!6si.g t linkag. ittdtl of ll ?a cM (Fig l 19) TlE

flmili6 Efinirg th. DFt 72 lro 3hostd . profound ldcl of l6ins losi whil€ the

fanili4 th.t d.ff..d rh€ Dli'Bal bdt snowc<t nodmlc to se@ h.rina 163 Trc

candi&te AoG in thc Dt-lvral lik gc i!ri6v.L ?MP&!S9 .td r'Z{/, q@ !.qua..d.

blt no mui{ion wa found

An int€rclting fdtur€ ssdilI.d with rh* l@i, th. noltl ,1'lVAa1 dd th.

n vty ..6ncd DIrVdZ, is in dif.d@ in rlEn ud@.ric pre616 This dv hdP

denn. $ft bdis for gemttlcphaotype @r.eJrtioro in dehe$ The @pting of 3

n@ l@s Dl.fVrE, is dsi$.tn v h rh. i4 thlt addiiion l dd&.!s@nig l@i

rdin to b. 'u9d, and splotl tlE hlToth6i. th.l tt P jsld population b th' best

euc to srki in thc iddiid€lrion orth.€ rFrcs.

INTRODUCTION

Audirory dFfutrtjon is Mif6r.d ty pdrial or @npl.t iMbitiq ro h@ or

piopett di,f6s id. soDds, ad by r.du€d Dotalid aor sp..cb n lhe all*r.iinlividusls It is one of lh. mosl pcv.l.it so@ry-neu.al d€ficils in nuur4 !d dlT*ts0 l% of lh. popllrim @nd d. Abo[ h.r of dE ce e @ic.\ hdiLbt.lMonon rd N&€, 2O(X: D!u.d. ., a/ . 2009I

TrF 6B of hcEdi&ry lEing inpdrnEn nsy b. lt|@seic or mlheaic(Babuntu ?, al, l9q; Fnd|M dd Cnfi \ 2003) Aboul ?O% of rhe hd.dira_v

66 ee non-Eldrodic \ts4 l0% e E dronic. in liich d.afn6 co,oau6 \itiorh6 tflom (6orlin .r al, le5; Kdlsir md P€ril. 1998) Th. ede of inhsitued4v b€ elo$hd t6sirc (75,300,4 or cs), @r@trEl domi,Er ( I 2,2a% of cB) orx-Inr.d (!-r% oa cs) *nib Y-hr.d !d nirodo.dn.l d..fr6 e atso tod.d(cr)6 @d Vd Cano. 2004).

C[.ic.lb, d..ftB nEy b. clssifieit 6 contucliv., s.@tuurd or mix.d

ecord'na lo lh. siie of6. def4t (M&uilo d al, 1993) The sq.rity oth€dins lo$ is

|@rd by tudiom.lry ed 6 cl6ili.d inlo vdio6 tacts bs.d on lh€ atitiry of a

!.Mn lo hd eunds of difad nidily a v.ryi.s ftquodB (BEn6, 2m6) Thel6€ls of $vdity e dlfdincd i' o nitd, trDdrar5 we sd Dofo@d (Mlmti,,ar, 2003). In Co@tic danBs" rhe aubsom.l lsive fom of heins t6s @ rlE mosl

evft Thq @ ty?ic.lly @nssit l, bilarsd ed ftly porcldt smrireural in

@n@ ed e. olmosr qduiwt due b 6.h!@ def* (cidio erat., t99s) rn @nl*(dE anoso'd doftin in fom of {te|'B & samrly Dosdinsud, prosair !d eo8a undr.l or mild bilddil, rld c.e borh @dudiv. qt $gdrud !dno,6.fi&<rim (F66., aa. 1976: peri( l9 )

c€nsic ed nol4ur{ apptwlB ha@ prova to b. pow.rtul methods forud6lodDA lhe plDtsiolory of tsirg rn p&liqrle, th. idotific€rion ot 8o6sDKssl in th. imd @ ard dE sn|dt, of $c chdlisr_v ed plDsiolos/ ofde prorciB

nbded b ln6. gc ns b€r very fruidul (FriedM ed o'iffo\ 2oo3: w@& ,, at .

2006). Idivdud! *ilh i.bdn d udnory dtdndon provid. t uie6 $os s@ asd md.Nl&i rh€ir 6ndim dd @de oa *p6i@ (R.jrno.,1992). rbwvd $is t&sk is ompticaLn due b dE exteoe saetic bet@go.ilv &dlinired g@9TdDhtuqpe @rrelrlion ol hsEdiEy d6fn6 in hl|m (pdil e/ al,

2001). ll ha b6.di!!t d |htr.r 16r l% (-!OO) ofhufu prcLilodi.s sgE espailidlt hrclv.d i! th. ndiB proc6, .d tns rDrrlioB tr r!'y difi.d scc@ 8clcn !n didol harog4ily (Frinm id criffiti, 2003; NrE , 2m3).

Cliii6l h.rslg4iry i3 .vidal $tF n'r.lio6 in 0r 5@ Ba ri.v c.e DFtrrd@ic lllourd 6tv., @$ni dorind d qrnrcdc d.!K fdl'mpf., ditr En an i ,llda ot WOTA r@ jt@@t tgiv. DFTVTZ

dr@n l doninar ux,r // rn trdremic L6lr/a (Li! ., ,l, | 9?4 Liu r, al, l997br

Ltu a ol., l99rq Li! a at., t993 ri wd.,ar, 199?) MooE, rh. e6iry oflEi'A 16 .lo iFs lsaeS.ldry. Fd eDpk, rurr.lH€ of Gra2 (D!Urr)hEbofot ro de hdirB 16 EginS fion dtd lo p@forld. .6 in dE {t6i.d

'Jmbds of fh s@ tDit (Ddbldfo .t al_, 199: tnvpi| a at., t999:5.b. d at..

2000 !d Snch d ,1, 2005). Rsi* ll,rr dld6 ol $m odE 8G h.E .boba r.toiLd io ..@ pbfourd 6 *dt 6 iod.lr. io s@ .lditory drltEuion ar.,Sl,C26r1 lDtNR./ )t\ (tn.@-Eie6 a ul, t999j Nqtar.t d al,2AO4), CItr2J(DFrVrr4 (C:hib.,41, r!r96b: w€.frn.t a|,2@7J,fEU (DF|D2| t O1z d al..

2@t , otoA <DFNB22) (7*ry.d.t at.,2@2' d rcDEt5lDtNB23) (rt r.d.t

To dlt 138 utaom.l lbrrdMi. tEir iq,nrrsr lod hn b6r dttE!?on d or |g*d. At49ofdE lci, ttr tutd slE h.€ b€rdqiddql F n.

ea ol lF locl (22 iddi6cd g6) e ssi!.d *ith !r@!d doMltrcnisio *tiL 3I lqi (2t i.bd6.d r.g) dFr -l@od tqirc in|,ireSn x-L*.d lGi (w jdlrrilid ga) tn $r rncrbdri.l saE he. d$ ban.?on d (Hrqlidy [-ias 18 horEFsc h@r/*talot.r-b.4$lt). Th. .v.it.bt.8a!dc htormria iidicdq 6r ddjd@t datB g.E G F ro b. '{!.d *nitr..quia lunhd iiestir,li@

I-i.r!e. dlFb of 14. qs4utF6 feiti6 lnn irrEibd daliB hspd.d ro b.$.nahod ofdDk for tr'{tirB B lci ieleld in lEinS np.rtfu({d .Lo fd t!tuiu rtB. li'*!g. i'n w.r5 ro id. i& $c mdr|d s@ (p.rit dr,l.2ml; F ntm rd GidirL 2m3} Tn p.ril|.ii poputd@ olf,a , q.otioEtpopuldd ro aty o trr.8. !dr!b ba4 d. ropddon i! diia inro dif@lIrib.+ chic gD!p6 rn G|6, rt'id h.v. t ray hgh lcxtsr, of hbi!.diis.d elildy to b. daiv€t gcsicl|t homA.e6 Aryding b r @d cardr d drP.ld.r.ri Fpd.tio! 6Ot6 of dr |ui.86 @ dloSui@ur ot rti.n fiE 0- m%F b6*e fial @Gi'! (HNnr !n Bint.4 199€). R6ivdy irlEn d dis46 e

mE psd.r in @EegliFs populdoc (hb6 '/ a/, l99t) Tht B 6id4l noh

de pFril€@ of dsdild j*sire d.dHr cg ir d. Pstisfin poDulato4 whjcn

e 6drnd.d ro b. I 6 td lmo, td ?ota of|i6. @ di$ in oBnarnnaa fmiliB(Elohi d, at. 1993) This ha allowd naDDins of 25 allosonal .€6ivo de5fE3 loc'

nd dF id.dincdio of 16 ssE b Plkaldi populr jm (Hdedtttty haninS lNnomplsd htrD://*bh0l.ee.bo'hhh) ed hB add€d cmidslbb lo d'e gqFtic

infomri@eE.swd..f6TIE nrajor obj.diw ofrhi! study wG lo idd'li& lhc ml@ul4 bsis ot ednort

d6frD<dd &o!!d sith ditrsd dnionaric DrofL* c/hidr dld h. hdtaul in

dllblishog e@t}lFphml,Te orelali@ in $n disrde ro ehi.ve lhi! objoclte,

50 f&dl!. s€gr!8ltns rrGord 'csirc hsEdiLty hdi4 lN re @[ed DNA

ws dt@l€i fbm bt@d spl6 tDd t &!ge E FD for |ne l oM dio$t'.I,tsiv. datB lai s pdforn€d d 25 sd..r.d ftnilis Fou fanil6 sho*€d

lin&Ieo ro th@ publth.d loci tL DtNBa, DtllDT/l I al Dtlll29 Sequre .nd).8

oa tro lirl.d fanili6 G lbo D.fonr.d enirr @i!d in lh. iddi6.ni6 of@r.oon d nurario (p.v239D) in $e SLC26A1 gN

^ n\. DTNIN l@c ud one mvel

dllrid (p Ag,tv) in crrr' s4 a lr DlnB2g lN.In o etfoft ro sch for @v€l loci idolvln in &dltorv dllfildto4 .3@F

*ide s using r33 nic@rdlll. mtt6 6 pqfodt*d d l*o fmni6 da sho$ed

rc linlagc !o lsDM datB locl Tte lsDtr M Bults in &tulv PKDI335 h€lperl

in |ne dbevd of ! @ l6.iv. daii6 l@rx DrM72, o d@I||o.@ 19?13 3-

13 2, wilh a criri..l li rSp oienal ofo.?4 cM bGnv€ th€ ndt@ Dl9s2l6 (d 20 0l

cM) ed Dr9sro34 lt! 2o-1s .trD {^n et al. 2007) h addilioNl dpdiDats.

rcfuEnF|| orDl)vr72 rc wri.d od *in d! h.lP ol tst ddetEd odts !n No

*s teili6 (PKDFloa3 {xt PKDFTIO4) [tr.d io llt DF]VBZ clmtusomal Eeion

Th. Efirkred irdioLd rhlI Dt?t47,2 M a ha@8qeu lo.ut hsbounng l*o

ditrsqn l@i d. €di @ dE Dqintl &d dind dis of uE r.tott d linLgt i4tavd

This EuI.d in dE ro4pins of . @ l@B DF r3l (d6isnar.d bt th€ hlM 3d@ors@izdid GruOo) @mim) d l9p 13.3 6.tu Di 9S373 (d 6 57 cM) 3,i D | gst I

(.r 13.35 cM) agot65DS. dreme@l id6/d of II ?3.M Thisds@lt d in

rhe efiftnqn of de lirl,se boudsi6 tot DINB72. rcN b.twd dE ma*6

Dl9slo34 (st 20.?5.M) dd Dl9S39l (.1 23 33 cM) spei.s o hisv.l of 3 03 cM

nE.Il6Ld indrvidn ls in dE fmili6 d.liniri.s DFnrNr 3rbw ! md..ac b sd@

&dlonunc potuc *lil. .IId.d nlividuls of ldilig tuepcd b tctdrd DINa12

itllsyd h!rc prcfoud dat6 The min@ IOD sE for tlE tlhily PKDFj043,

d€dni.8 rFnB3l, wa lodd !o be 3 59 (! I = 0) wirl rhc dtd Dl9559 | { al 9 34 cM)

*nib hnily PKOf335. eni:h sb..cuqrt $pDod.d Dfivaltr, $osrd ! @imMLOD sE of 4. l0 wii lne dtta D 19S424 (d l0 97 cM) md D l9sr4 (at 20 0l .M)Th. LOD src of loily PKD' I lo4, r'iidr iefn d lL DrxtT2 inhd 6 c€lcrtar.d

robe3 Il fdrh.8uidDl9s934(d28.6?cM'Ila tefabn DFNa72 atn DFNBSI diti.d i.tdlals {e locatod io a etu ricn

rgio on chmMr 19 (UCSC CrFft BioinlonEIi6, hlp://Edtu.lE..du4Son. of dE EcB Dc@r sirhin rhs loo @ 3po<t c&di&I6 aor ding $e ddtn6s

phao9le Two inpone[ s*, I]lf,Rlrtc ed ,zRl, s@ s.qucE€d, bul m nuLto!

lh. nappin! ofdr nd l@6 ,r,,va3/ in th. P!ki.l4i populadon sub6lamidc

rh. lD1olh@r ll r svq"l smh lai e nill io be idanine4 dil {!1 rhi5 lopuhtion wiU

tguin hdotul in |he ido!ficdron of lddirio., G of d..fK This 'datific{'on

wil sitl i4 dF unddredi.g of lhe n4hantu ot hdin8, qtich in th will b.

bd-fti.I io rh. i.|p&nd huju b.i.F Tte t*! dstEdr.d toa. DINB72 dDFlVatr. @ ssid.d silh difrds ludionertrc Dbfl€s, &d lnc idaninc5don of !rGiv. l@s f6r nbdr.t !o ffi uditory dFtudid qill @ftibut lo 61t!lish

|n. nu.! d.sird gooqrephaoq!. @f,dlrioE in h.redibty d.inK.

CHAPTER-1

REVIEW

OF THE

LITERATURE

sEcnoN-,

THEEAR

ANATOMY AI\D PHYSIOLOGY

I

l.l lll^tlouY oITtfE HUMIJI EAX

Tr! rl|ta &dilory stltatr ir ergri.d oa. nF.l @rpli.a.4 rt Srr.d dlng y sidv. .ttrduE, @lLdirdy drFd ro B ttF r, *nicb D.f@ t dudfrlldiN of hdiig rn bdr€. Trr hrIn d 6 D@it. ad disiniDr! sqb !rt qEi6 Er8ii8 tioD 20 io,,00o l&.t (D.llo., |996; crrd rn JohEoa l99B).

Tb d L dtpo!.d of thc rioniql oopara|!: rb. odEDl a, dtdt.@ $d

'|E d. Tl| boujry b.r61 |h. araDl * rd 6c niddL * i tt

IrnFi E hE *li|. d. boud.ry ba*6 d, Ei.LIo d lid |tr inFa & rh.

Tt oI- & cGitE of d. uid. (pi4), th. andrd lni&ry rEns (doql) dd dE 9Errric r6$tu(d{@ d Dtnpjd) (Fis. Ll).

A piE ir.!.crd d ho$ |!.rt sid. ofdF,tu! b tirlFrr od nud6Tl. PiD @6i* ott dri||gi.oB 6@*qt of dsrt dEiF dc 6vq!d *ir[*in (FiB. Ll). I s6 ro dpl@ dr sd|d strs fon rl, anrdnE d diFc!.

r.r.rl EtLd.l A.at tM.d!Th. .ddl .rirory .n6ra or d dd i! . tunrd-E l!b. ttu 6!Edr dE

p'm |,o d'. gDpoic nd@ (Fig t.r) ! ir &ut 26 tu i. tasrn dt r m indi@i6 .n i! [rd ridt 3qEb6 tcrbird !?itbdi'm, idr od.i! r.!@6glrds .rl h.i6 M irs a|!ie &.?.. ddin tu Eds G ti. tui!.q sttldt{a !.q!. dI@ (r l[) !n d r!a. d. tng.M $R ed *!rD@t !dF.vEnt f(ig| obr.6 nlD Fdi.s rt od|ur.r.rJry.td. M.!b!D

T'| rynp-ic 6$d!,.ho IroM ! dE oi^4 i! t din 'nb.c Bni:hs!d!. e algrd d t 6 tlE diddt - (Fb t. t) tr lca !. bjia ro DFrerrgt'id pnho86. vibdi@ of $. rynodc nFEh@ trGnir ord tom lh. dr lotF did- of EiUL -. RltnE d prfodid .f d'. rdm 6 t-d b didi*

{d

r"lirii:)*'--**--

l-"- t***t,*.-dnor}4.b!d[

The middl. d is a naftk !i, tithn qvity lmrr€d bqw*n tho ours and nncrer. li ts epa.arcd tun rfic .xGnal 4dirory tMB by .he rrmpoic mmbdre edlibm the inner oo by a bony pannion, which conoibs No qindow\ d olat windowlfetusn venibutit ud a rcud vnc[* Cfere!tu .uhted. Tne niddre q h ,t$conn*red ro lnc r6.ph!.ru by o smal lub€. rhe Eusehie tubc (Fis. t.t). Thisconetion sts io equtia an lGsN on bod sides of rhe 9rpmic nhbdc od at$allort frcsh at cnter lhc diddtc d ovity. t.telions of dc Esrachie rub€ €!$aeumulrtion ol fluid in $e middte q sp@, Esxing in o coturirion *noM is orirismedi *hich nly lstl in haing tN. Tie mosr impotui studtE or rxe oiddtc 6r!rc |xe ln@ audirory o$ictes: incus,n.lt.6lnd $p€s.

Thc $e auditory o$ictes ,:s.. molt.6 (h!mmer) incus (!nvil) d slep.sGritup) @ pled in a sid in lhe niddle @ c.vity. At one e.d, rhe mllteB h lkhcdby ligmdts to the tlmplnic n.mb@e. whjlc .t lhc olhcr fld fie n p.s is conned rorhc oval windor of@ht.a (FiB. | .2). The sbp€s h the sm.ltd bone in rtE hun& tuy.Nghly oa lhc sin of ! gBiD of rie. ItE tundion ol.lhc o$iclcs is 10 mDtili Md

9

ft.smir e!.d rav6 !c6s the tympdic qvity i@m fie gnpsic m.mbtre lo the

Th. gometric.l orgoiarion ol th. o$iclcs .nd thc su.f@ !g difeEnce

b€rwE. lh. tympdrio n.mb@. ud thc o{l window 8iv. a N.nty fold mdifE tion of

F9 u ft & * .dd.: rr4 r.r -d rF r..d !d & 9ir.*cdry,n.bFi!*JLdF.dd ift r|. o-Fr|. .rbnx (^d*d rrr E .!dordi' t ibria

Thc ims @ is . mtld $ere drr is bori.d d6p wi$in lnc Enpo.al bdlr

of the doll ind is @rdt d *ith dul tuncriod oflFlirs a wll a Nin|linins b6heol lhe body. h onsiss ol No pm.: thc bony o osss l$tainlh ud th. mnbmoslabyri h (Hudsr.b 1989),

l.rar Oslr trbyrintTl. toy Fn ol lhc imr d is kmM s $. osss bbyrinlh- !t is fillcd

wnh a nrid kt|M a p.rilyntl. ftc ch.miol @p6ition of thc Filynph @bl€s$n or$c ecbcpiMl flli! in which l||cr b l@ K' {-5 6M)..d high Na'1-145

mM) orcnrdid (Gnhm zr al, 2000). h dsi.t of rh@ m.jor uromiol sccrions:

L tL fioniil ssry porlio is dE Cerra - ! bony spiml orgu with 2rl:

ums, about 35 mn lo8 and lmks likc a e.il shell ilhus nucd "c@hl.o"

mdins $.ili in mio. cE.{-). Th. @hkr is its.lf divided lenerhwis

9

trlnsmn eund rdv6 8crcs tne qdnp.nic sviry am th. iymp ic nnb@e b {r

The el.odnd d8@idim ol ft€ Nicl6 !trd $. s!rf@ '€ difcneb.t@ the llmp{nic nmb.de dd th. ov.l windN give . t*frty fold dplifEotion ol

F€uftrsrd+.r'||qL.qId{F|dfue'4ddry..t.bF{brr..e.fu tna ||. irrFn rdb'u (^d{r.d rr- Exr.hF.L sdo,rw.turh(dl

'Ille inncr ar is ! @mplex shciuE rhlt is hnied dep qilhir lne Ehpodt bo.c

or rhe sloll rnd b ..|:m.d wirh d@l funcliod of t {ins 6 stl $ tujftainins t6bEof the body, Il o.si$ of No Ftts: d. bony n (rsx l.b"inrh sd rlE ncmb6m6kbrinlh (H!dsp.h, 1989).

l.l.3.l Oso!!LrbyrldthThe bony p.n of lne imcr * h IroM s ih€ oss4s lobsi.rh. Il is fiU.d

w n ! fluid looM a p.rillDph. Tte ch.oiql @nFsnion of ih. Fitynph Mbtcsthol ofdE aEbF-+id nuid. in ehich $.8 ir l@ K' (-5 nM) &xt hish N!' (-145

nM) conqftrion (Guhd ., d, 2000). h coNkts or the mjd e.loni@l s..lioNrl. fi. frc d $mry p.iid ir de Ce?r&a - o bon, spirat orgd win 214

turnst .boul 35 nm log dd l@*s lil@ a smil sl'.ll (lhus nmed.€ehtea,m$ing \Mil" in ei{fi c@t,), The ohta is ierr divid€d t.nsthwie

hb rh@ chrdie: tlE r@/. Erer!.i riicn h6 $. o$l windo$ ar ns bettatula |m7ntj *indaisittcmEn vindow: &r., rh.r@btrr'ra

"nich.oloB lh. tue lFriie s@ry suud@ I e, d. o4s of Corti (Fic, I 3)

2. Thc @ p&r .Giln of rhF si<iftulr @ds (eaqi,i ldcd odpotu'or) whid e oriern d { rttd aigl6 !o d.h oth€r axt G liruFnposI4dry (ddslt) to lh. Etihie (Fis. I 3)

3. Inlaom*ri'e dF Gl'16 r,i lte smi.iEuld cnhB is lF v6libul., st'idris d'e cd rd pd ordF booy lobrurh @llinins rlE uricl. od @u1q lh6

reor8e GpoBiblefor bdtEl.lj,2 MdbnDc r.Dyrl b

M@D!u6 l.bFi,$ Ii6 widtn rb. boo/ hbrridL Tlt chtnds of dE

tunbr@N labldDd e 6[.d Birh I tuid qlr.d o|dobrpL *iid ta E6udompc'ri6 ta, high K- (-r 50 nM) nd lo* Nr' (-t.3 nM) ctr|r6irciotr A5 r r6utor rb. dirs@ ir idic @rp6idm bdra dE re @nDsnndE, ln.de.tochdical pohnirl dif.l!@ bdw odobrph rd pqibnph ir abour +ro nvThn n dE leged podin* polarid .litr@ foEd in rb. body. SiE lh. hr&.ltutaGrins pordi.l of h& 6I @@to6 t eud ?0 mv, d'. Dot€dri.t ditr€tog

':lNdE b.n cdl rtq i! EnEt bh ie, 150 hV. Thir lISe pola|ti.t diodae sgG s a

lEDadN idic fo@ ro d.ire dE n!.lEDd..liol r.Bduclio pro6 of dE h.nelk (Eis d R'14o, 200?).

A. intorLr f6n& .f dE oiolynptdi. !!c is ld ir ; @hDtd4lv bofrLdby dsB, di 0w @ rc du.rs or opo omeliN b€tw) pdibnph ddadolFqh The bord- bd*€ e $o tuib li6 n rh. t rd or dj. juEtiB b..l@di epitlFli.l elk thd 3utrlund in ddotn|rilric sDc. Tisrn judi@ ir 0EplE€llulo spe ot epitt lhl c.!s dinlrir dB gldidtj of Na'ed K' io6 alMgd. ouid onp.nr6|s of nE i'e s.

n&|.}rftfulidr:o..[|d'rrn6!.rbn|uh.''b6tu Larr$ e s..,rr. r 6E Erd.EL!

-5 & d d

eddct.|..r.crcdlr...d|aful'!.'*t.''j.&

rft .E t.!d (Mdd tul

ThE 1lF3 of .tideli! sm!'d tF 'm&uru hb,irnn .idolrnDl'dic

mFixd rt dE sst rtitldi4 dE ih ''qarFitHn

tn k speidiDd.riddil. s.brt .,i*ln (Grdorn.rd.a6)

Th€ ffiry .ritlEli. lim th. speific @ of rn. E$.diw tuEi ehich eeQonsible fd Me of pGition md snd. nE s$ry .pnn lal lini.g is p.*nr@od i,'e M&ul& of tnc ueicL ed sule! the rhe .rrda @r,,r!@ir in $e dpolbof *h sicirculf drc! !|lt !b. orge of tui *ini. ln. shl6 du

TIF min cmFEnts or $lsy cDidE|n e lEnDd.Bduq h.ir ellr Th.ssy €pinefiu k @v.Fd by lll. rdori.l n.hbMq Tn. site or h.jr c.n !&sdu.tioni3 o my or sicc@ilia tnal pojc. iion hair ells, @g.d lik !sloilw in mls orircEaing h€istu cdl.d 6. hnir budl. (Shotrcll e, al., | 98 | ),

IL loTn-Don EDrndr.

A ved&.pidElid lrld, dr. rrtr k@lei lim3 dF r.urr rrha oa@hl@

t2

6d $e dod{ ccll Egio.s of the yenibule sy$.m. Thce rre rhe ion tansFning epithelid.

which aru invohed i. acriye tlrq'on ol ions ococsry lo maidoin rhc unusual

cndolymph cohposirion.'l1]e ',iz

ut da! is @mposcd ofdiR rn€s ofeus rhc

margjMl cll: the intemcdiorc els .nd rhe bael Elkiii Ld Spci.liz€d f,plil.lir

'1tu le$ spei.liad .pithelio includc the Reiss.er's mcnb€nc in cmhlea ed rhc

cpithelio lining rhe tuf of the sculc. rhe uLicle ald the mpulhc oade emicircllecoah. nr* cpitneli! fom Fdability b.rie6 ep..ati.s tte fluid $€6. RupoF or

ihc$ mcmbdes w.uld bc expeled b rcsult in fluid miing and physiological

The atility oa iumd dhld ro d.kr ed dislinguisi oon3 difeMr sund

fiequeDoics is pnnarily based on the snery epitElii oflh€ organ ofconi. situarcd in

ihe middle mp.nncnt e,t ru/a of the @hlca The o.gd of Corti is lhc

*n$ri.cuml cnd o.su specillize<l for hwiry vhich rmsdues ound sves idoelecticrl impuls ll is mmp.sd of polai?ed epirielial ccus Oan stk rnd supD.ni.g

@lh), I sp.ciolizd basild mehbBne, audibry neRe endin8s rnd thc ccrorial nmbrMc(Fis L4) (En8slrw e/ .r , I %7; Ha*kins ., d, 1965r Kitochi ./ ar., 1995: Smid. 1968r

SFrndli., l9ri WeNll.r/, 1965).

o@rorcod;sh'|4hr6ba|l'hedo'.nb hurn r rqr/ tt'jd.r.b'r}

TM t}T6 oalrt cdb @ pr6dr o dE o4a ofco.!i, inc h|ii Elb {[JC) edout6 htr ells (OHC), shi.l| e quiL dilt@t h t ir f@ctionrl rdony. At bin[ inthe hl|@ @cNeE thd. e lbout 15,00(!25,000 OHC5 &d 3,500 lHCs. Hrir €lls do

d Ia ! lif.d@ ed do DoI Esar.rr. s,no bsl (Slom,,,1, 1993) De4e lo dehlir cdh 6olE in dd@.d tsing $itivily, ia, mriEurl hdi.g l@. TIE

iMe. har @lls m dF tru6 so'r cdl!, sdnB inpukF ia rhe .uditory ndq l{)ile

llE ol'a hir cdk e Ecd ro d'h@ d'c psfo,tll'e of dE @dJa by i@irgsde.rivily (qudilai€ ai'@ ) !d iE6i'g sirieirt (qrdirniwnhoc.Mt. Thry e ffied lait @lh" b€a@ of th. protuding tufi of slersili!6on lb€ Aic.l dou; ofary cdl (R pnrd &d Alts.hlls. 2003)

'Ih6e m cliindn.el cdh 20 rM to 70 rrM lo.g ttu bave - l Oo slgacili! .r dE

.pa of.idr c€l, &d a nuds .r t|| botron. 15,000-25.000 OHCS de qul&trmepd iI nod @lid ^o-l Fj wnnir &E or $diG lq bs fodi'g !ch@rdirric lv strop. (R ph&l e, dr, l99l j Rlphel &|d Altsduja, 2003) (Fic I5.)Tb€ ouro hajr c€lls hlve bolh s€Mryd noror dnds &d coinribul€ io hsngsidiiry I t qEEy rd..dity by !rpt'&i.g $Ed

'loction G.rliFra rd

hE hrn cds nddi6 a g$ry cl@€d $tid @Er sod-bducld Dri@or tL. bail& nmb,e inro dE .l.dtrlEicil lom or i@ iftputsg. T|E_v Gdftrged i4 t stlish liE or Nid. Lr snq. lrl aom r @druous eay of

4p@xirurely 1.500 ctlls .lo\g lh. iffi ponion of dE orgd ol Coni (Fis I 5b). E&hitu hdn cdl is par sh.pcd lh a @rd!r loaLd .u.t4 &d aloul 2G50 sic@ i!rud. of -rih filelrd d |h. lgi€l surac (B.des, 20OOi Psnly dr al, 200tj Sl.tcryst at. l93si H&hrey d/ al, 2000). Tlp 8piod ponion ofhrn eI5 *ittr llF 3l€|wili.cd6 in E rela r&16 (qnobnp[) stm 6c betale.Nt ponim r bd.d in

Filr9t (R.9rrd dt AhelnJ6, 2003).

Th. sl.@cdia d. drus€d i. th@ ri6 *nn im@ing lFidn o. .!.r' sucivel6'd (IiB I 5c) (Pi!'l6d ltd Al6ddo, 2oo3) E dr li6 is dr'.o.d ro dE Er brvsoa 1}t6 of lin*s enicll oirai. fib6 rEde of Espn 6d fi,rrrr, DbLire (Bdle e,

dr, 20m; F.uiprle !d H!.h.J/. 2006). Ths. link irclud. th€ followirg !ps:

l4

Tlp li.k!' lnd mMr the dp of dE sh..r.r tuilia ,o th. side or Ihe adj@rlllLr $etwili., This almgdor is b.liaed lo bc Espotrsiblc for op€.in8 .rd.losing of the chm.l g.1c by e.$ring onilom cxcibiion of ih!nEheotasdud chreL (MET ch@ls) (Pi.kEs ur d., 1984; Flms ddHrckrcy, 1935; Goodrd s, al, 2005; Fl@k .r al, l9??).

TnnreE or lonnl |ir]r !it!.h st 'wilir in lh. m€ w dd ftom bw !o

D{ (Ased .r rr, l99l i Sheph.rd dd CGy l9}4i Pic*ld r, aL, 1984i Fun6s

3d H**ney, 1985i .tlcobs .d H!.l'p 6. 1990).

an&le li c which cmct sr.€Gilia ar th.i. pbximl .nds. Th* linls eab*nt 6w rne h.n elb ofinl orSd ofconi, blt e pltgr in rhe hln bundl6

or rhe v.sibolr oBds (Cslrc s, ar-, 1987; Richlds ., d., 1990: h.obs rnd

Sh.ft .otrn.croB I pF$nr alonS ihe niddlc region df rhe $ere@iliary shaR

ToC<!!.etoE linl tuili. lae..lly jN b.low rhe Lhl of d. tip lintr

ne. E G, oHG blrdtr. rdD I turrpFnEdtnn$.hdrvh,u ihrF (.) arn4Earorhirdr.|tjdrl

t5

1I PFYSIOI,oCY OF IEE TfUI'AN EAR

Inc llE Frrs of 6 e dengn d io c.dEl s!'d u6 ddeh lhdFimiFny dif.@t m.dn ia, tir, bo* ! ltuid- TIE cqdsr.d s.6 c mEr.dinb .L.iric.l lagmk tl'mgh ! si6 ofmDl* n p6.

1.2.1 Sourd @ducdo! p.tlnyn€ tud *.€ c collctcd ht d. o(hd o $,li.h phF lhc Dlc ol o

radic etcm: rh. pim (bgcrt6 *id rlE had) dift&rs .nd fa|s srd mc*liib 6c mh. .rd dd$l trdibry ftsB .d s |t$lo6, ft. 9Dp.ric mdbr.Edthe@tdtuvib ..inEsp6n$rosddpEs@rt*s.ndEehitsmEm.rs/rotodl€us of $e ntdle a which i. @in.d.d ro d€ inc6, Th. incN fttrnd ioim th.

staF .rd pur! ir in b*k dd fdtl nodon pustins lne ovd window in 4d Nr ThG

mvl'tEt of ih. onl rirxb* $ts up 16 i. tt FilFDh oldE sdowntuti s.@1. rh. b.tilr t|ht e is ,o5r!od ine.td. .rd hrle6 inb tlF salz Drtpora,

i|mi4rn pEffi orlh€.trdolynph ici& d'e €d'l6 d@r (Fis lO.

rJn'dc'iffim46

II

l*.- l*-."I-"*it 16 hrur or nr. dq.{-

'h e n.br qrt dd nr tu n. orFr. E||- tddr.rq|Gaad.r.krir

dedird.l.dFt.Enl|'*FI'il.do..jtd.}i.-a h rrra- .a r* rrc (..+. h rxrd.r.a. b.r-rr.rn.,/ r'.!.|bj.')

l.2J Mcbdod.rrieltuldu.{o.nE up and rioM vibErioa oa baile r@b8F 0..d. a st@i,s loE bdwM

tlts b6ile nmble ad |n. ie.lorid nmbr@, rhu cuilg lhe sllrwni. of thc ouldhrir cells of dE ors4 ol Coni 1o bard This dwins &lion cu6 defl€rion ofntu i! b@dlq *ldd' oFa rFddjcJly sr!.d id clEwls loer.d m rhc ,op ofa.h sLlaili. Q{udspd l esq shoi}dl ., ar. l est )

Due ro rh. bieb .oEfinio of K in didtf,ph ad slorg Ecdirc pola i.t oa

t|. hrir €llE K- ioE rush i.io d. |l.ir cdG. nit 6ds b Mhtia eE of d.n erdve d4e ad dAol{i4 th. IEb@ ol h.ir cdls. Exdr.d (deolaiud) OfiCs

r*l B c.ntdrq (a phtunldn reM B d..nomdliry) llrcucn o dirc a6ponndhdim rh!1 iNofve dD pror.in wstn tt"ih4]@ et. at,2$D, DE b ln. lishr

auplin3 or oEcs wih rh. bsild ndbro. ed raicule lmino, 6i3 &riv. nt .hsisnr*ds oer&/ b&k to de ors& oa Coni dd th. Itics re trit d due lo rclondmcnbre i.ti*lion of st 6cili! (Hud.p.lh 1939: Slrlldl .r ar, t93l ).

voltag. minve c.lcim dmds c ..dd.d i.IHCS, dd c€lcium sigS.ts ih.rdee of tmtNiih (@inly sl mtr.) !1 3yrrr66 lilh atreE* udiior! .@adiur ! rb. bel dn ofih. cdr. Th. idpds @ ps.d tia tu c!.||@ bEdr otriE Bt urc4tr@ Od) 6w ro ln. n d'nh F@ d. @<tulh inNts r.v.t to

tlp nidbEia lto to tb. thr|lhus, ri fnnlly ro rh. ediro'r @ ofdE rflooel lob. ot0E ccEbr.l d* Sou'ds oa dilI.rat ft.q6i6 {ire ditrsd '6 of dr pri@ry

udilory olDiex ordE bEin (Cill6pi. !d Con'y. 1997r Pict!€ .r aa, rq4; SLd rdrs,2ml; Stel,2002; Slr.s@i.r od CiIBpiq 2002j MrolNti e, a?, 2006:

Pet€M erd will.m,2006)

1:.3 FcqM.y diltdb(ton rlolt th. butt.r @nbd.Sinild lo nNic.l iNru@ls dE odto is . iodoropiodb lu.d oryu (Fi8.

1.7) TID b6* of th€ od a i5 tut Gpo6irc io hgh 6-.qFcr $utni rn.@ lh.q QttLotut ffi low 6!qu-ct $uldr rh. i@ F lg a vsict ofrEl'ois to a.hid. ltis booloph sititt, jetuding dE nri4 of dE bsilsl@be !r plniculr DGin6 dd'a ig logth ln addilion, ! Ejor r!.n!isinvolG dE mw b@d of |i.qu4i6 lo rfiid hlir cdls (Elca !i oHCs) @ nldr petculd posirion on dE bsils !Mb@. TIE exd prfen of bsild mmb@d.lomdio. is in'0orta4 b@e lhi3 Imb@ on&tG d* siliv. 'r.qo. cdh(h.ir cdb) *{dd rlcfom $ud Mv6 inro F. lnpotse Ar rh.6td of th. cNN..,closet lo dE niddle 6 @vily, lhe bails l1Mbte is r.hdv.ly slilt &d @or

t7

(rlpoxioalcly 0-l nn wrlc).'I1lc ndbd. b6om6 moE etdi. hd vider 6 n

drends thdsh rh. cahld towairs dE rFr (rgooiiddy 0.5 nm *ide). The siffponior ofthc membtue clFn !o lnc Fiddlc d qvity (b{e) vibE6 inmedi.tely in

Frpolre ro FsuE chm36 tusnitd b thc o*l sindow. The tibnlim tsn rhe

b& lhm ravel alona rh€ baila nmbMc loMrd its apcx (lhe ride end). Horev€r. the

Egion of ddimal displrcmor of dic b€!il& n@b@ne vanes vith Md 6rqFcy.The p@peni6 of$c n€mb6e ndrcst thc ovol window (be) aE such rhar it Esnales

oPrinllly lunder ecs lne |rrg6t deim io) wilh hieh i€qudcy toes wniG tne moE

ditul regions oflh€ membrane (ncr $c !pq) vihmle maximally in esponse to to*

'itq$ncy eunds. Ttus lhc rEqu.icios ol inc@ing eund woves m $n€d our slons lhc

baild n€mbme ond erch f&q(ncy stimulotes hair clls in ns chmcteristio plee (Fig.

1.7). ve.y lw rftguenci.s (< 200 Hz) d conprcsd on ro a Flariv€ly linit d siion dthe apial e.d of de mmbEnc (MMousski

", d, 2006),

orlrft.t|o..ldtr.q!ff.ynnbnicorlunrtr.fthritrdrprd

|l

SECTION-?

AT]DITORY DYST'IJNCTION

CLASSIX'ICATION

AND

MOLECI,'LARBASIS

l9

Df,FINIT'ION

Auditory dtsftftrld ii @if$rcd by pard or onplel. IEir€ disbilnr lnd 6

geddly @qiz.d 6 danB.PNf,VAI,ENCE

tlerins lo$, wn.{hd Eedic or dtDmcnlal, is oft of lbe Dorl pEvdalg$ry de6or5 ir hd|a (McKEici! 1992). Ir is .nimn d fta I iI 1,0()0 Hri6@if6l @sdil,l h4ri.e lN (Mon n, I eel ), oa tr'Ii.h .boul s0% e. due 1o sstt'cletoR lMl@itt et al., t991; Mond !d Na,.e, 2m6) h tdditid! p6dt$u.l d€rraalso qhibili th. s@ .dio itr its @6 (rorlrh ., al., 200) ) AsFElar.d plogBsive

lF&irg los (r'Errltu!) !|so nld I 0% oa thc popul.Iio 3t li! agc or 60 .,i up lo

50v, of indr'duds al Ihc .€e of30 (&vis, 1939)

13 CI]\SSTFICATION OF AUDITOIY DYSFUNCTION

Auditory dysimcton @ b€ cldilied m thc bdis of vaious c etu oclud'ns

rlE tT!. €. of oBd, ft.qu@y Enge ad 6@.rod

O' $o bsis of itTe audilory dFfuclid @y hs drdcrw ifrhs hdine 16ds froD drbtrr.lili6 ohh€ dlan l I or niddl. a, ot s€A..irc!'zl if |he lsring

16 6ulls ftln nElir*lion ori@ @ stuctuG (r:4. c..ltd) h4olsobertr''flh. hdnng b$ t a @mbindion or @ndu.liv. !d lqsriFral nrt6rD.rio6 cdralau.liory .lyfunction vnnch eolts fron de,se or dtsitrlion !l lhe level of lh€ vlll"c@i.l @e edilory boin sl€ta or ereb,t 6nd

Tlt o6a of audnory drlautrdon oay be pdang!.1 , t . MoF dE d*roD@l

of spGll or D6l lr4!.1, {)@ding.n r dE dev.lopmd of ernd sp*ch

o'r lh. bsn of i.quaEy. h@ing 16 is datned inlo:

. t^ nt{u.r t dtns lN i s, i..bilitv lo hd $'i& d frequ@i6 b'loN

. MiddL arq*cy t€tbr lK le. inliliry to lt{ soDds in dE fi-equary

6cl of 501- 2000 H7

. Hist a'qu$r h.i!8 lo$ i., iMbilny $ n@ eun& .t n quacie .bow

audnory <bs6sdim nuy be llt. !ol. svsploh in 4 rfdled indtridud. in *Iich

@ n is clsilied 6 mFsltddnic daf|6 N@tiitomic den6 is tlt N@

lBddr tu<t of h.ling los a@ulitrg aor ?o'4 of aI dF 8€nelicdlv d6i4iined csof d6frB !d is ottut ddGivdv g$ridd (Mon t! l99l: Rddd! 1992i

20

Mwih e! al.. 1993). In 100/6 of dE cs. datrs i3 fomd smd.d q h 0$6

'Edi€l nobtm &d is clsi6.d s sEdronlc d€:lK. Mor. d'& '10ro d€.''6_

El.r.d gdEn EDdbc h!v. ba Epon d in s{id hdiB 16 @y b€ @ducliv..

s6e.i@ol or mix.d (C.din er ar. 1995)

I.. CIUSES OF UDINOTY DYSfUNCTION

trelfB t . mltif.dond dientd 6d 6 t ..L5.d bt ddE 8aai. ddvnomnl.l f&1ou. or b.v onbinadon or borh

l.!.1 Ed@tl.tlgTte @jor ovnmmrd c.@ itctud. b&Gdd ai lid infdlio6 l're

qlhoid, rd46, naitgnn, bxodedx t|616, n!mF. rubdr., hca6 tirus dd

dlome*rloviru. Conplic.tjoN duills pt sD&.y or rur ans bdh aa @r@d

djaba6, t4?poxn q hyDodydra of fi. fdus, postuld bDt4 Fndll€\'rhroblsro$ !d fdalis nw .ltel lh. sodB or d !,i oe hsn8 h9lJlr@r

i' neDt6 (sb@oL 2006) o|hd I&lod lil. iodi* d€fciqcv oloroxc drucs ed

hsn fds ds qr$@ b lrds 6Frmn (Cha le33' Expo@ b loud me 6

de . @jor dwonmdd c€e of dealnds (Kowalsk! e, ar , 2008)

s[3D g* ml'lnos d€ th. mlt o|r@n s@ltc @ of h6edi@v h.@g

16 (Balciui@ d at, l!'gsi Monll er dl,, 199?), {nne dE drgoc ed @npld 'Dd6ol irhqit&E $ti.h @ re &|d drlfid]l to de@d! hw. tbo b€r rcPoned

fieynnlccl dd Yglt 2oo4; B.am arn xrE4b 2002)

r5 LE!€I,S OF AUDITOf,Y DYSFI]NCTION

tLrd.e il i6u@d in d{ibels (dS). Tht lhr6hold of 0 dB for a'r' fttquacl

r.fd ro lt ldd tr *nici midt r6us iulrs poEiv. t t@ busr 50"6 of dre tim

Hoe.s n co6ider€d nodul ia m individuol s $6nolds @ wiGin l s_2t dB of mmal

d"FtDId S.git oaheda los 6 8r.d€d 6:. Mnd h.{ht ls (2tu0 dB)

. Mod...L h.ri.t ld (41-70 dB)

. s.EE b€.r.c ro.. (? l-eo dB)

. Polomd hdrirg lo$ (a!ow 90 da)

I.6 STUDY OF CENETIC AASIS OF UDITORY DYSFUNCTIOIi

rrddbrdirg the tlDsiolog/ often'B hc bd a olDllaEr dle to @nplflqol il@ @. $,t!i.h s mogrisd ol vrio6 IrT6 of cdb, 4.n rdlritdy in stdl trmbd,

dus pce.lins lindr@ h bio.hdicd .nd pltsiolo8cai nudi6 (Frol{}ov dr a/

2$4, Adso a al , 2OO5t For Mptc th. cocl amb6onr, |u'huellselnch

ee diltrcult io i..ldc n i'B n dimcul o '.ldit ltr irioa ,blqE hw!.d i! rb.ir

frnction (ForsF orn wncn! 2002) O@ the p4l d4.dc, soetic &d no|4dd mdhods.

idolring d'. idd'dfi€lon of eqE drnsed in i|rF d a studid ot tlt pot i^o@d.d by rh* $16, hc b-o@ tlP prelenble strd.g,' for udd:ltnding c.dnd

nddr6 { lh. mlal{.d celd! ldd (Fri.dM on Grimo! 2001; w@ds e, a/.

2tu6, Indjldud! rrn ddnory dJffion rcpdar e oppon@9 b N 0be

d€f61iv. ss6 sd uIdaE d rltit tutnon ad nDd€ ol dptdi@ (Rsdcl, 1992)

Th. godic dpprosh b.*ad. is a dimcull l8l due lo lbo dlrffi Sdeuc

hdaoe@ily in lsr.dfity daf'.s3, sn ,D finir.d g@9?dpnmtTe @n@oN

kDs lor d..tB (Pdn e, al., 2ml) lr hG ba BlintLd |na d lan r% (_300) or

hung pDldnnding eFnd e invoh€d in hdinS ptu6s ard rubloc 'n

marry or

d6. Bc @ eG ld€l of tsits itrr9.i,lml ciba !n or $irhoul olE

5rprom (Foedry md Crifilh 2oo3: Ne€,2oo3) Bv uiie mldule ssEli'

kdmlosr th. chremsnd Io.4M of c ew e6c uddhn\g ttm svr ftmic

ann rdtr|dronic n€&rS los {t6.rdeu hav. b@ pEi€lv lod'd

Thi Epid ad!.@ in utdernading dE cq*lic c.6 or nutu hs€di$4

<t.fr6 h6 bs ad.<t bt d. aithbililv of 6h i6 s4t Crlj4 h@n3 16@npr*ilie. clinjcd ddA hldlv polForpbic cael|c mk'ri ceaic md Fdrs'c'r

drot|@dEl mp., gmtuc DNA s4q@ fo hlffi itn nic' tunpbcd.l!bs, ud by NNe dd zebo 6sh modek of h.c<!trv hdoB los

I.7 INIIETIIANC OF Df,A'NF,sS TRAIT

Her.dndv danK b clnsi6.d bv is mod. ol iiqillE in fdiliE a:

. Aurosotul rtBive d.dnN (Drxa)

. Auiosul dodimr d..nK (rFx.r)

. xlinted d..ft6s (DF7v)

. MnodbrnriddafrsTn msi @n@n Daftan of inndtle oamEvnenic do66 n &bson'd

ffiive (?Q's0o/6) *t!n on@nel dominn (l?_24%) x [tr'd (l_3vo) ed

nnocnondri.l inldrde ale q's| (Mono4 199!j R.!dd\ lrr2r Msuil! e, al.

tn3).1.t,1 Aoloord |t@lw mEyrdmd. d..|!d

To dd. (irdudis ttE pl!$l nudr). 3l M-rndodic lE6irc da66 singl@i hsebd m,pped, of$hich 6l hrvc b@publish€d 20 orthdc har. bm Bos€d

rirh uiq* los mDbo!. Al 27 of lh6.l6i, !t..!d!rc ssE r'!s bd Eporl4d

(It '!dila4

Hedig Los Hotkplee; HUCO @mitle) (TaU€ I I ) Th. mappei loci ior

mcslld@ic eloemil lEsiE de65 e d6igded 6Dtvrr. D|-NA2 tu.s@ oidr in *tidr drey *@ epon€d or r@.4 ed !.lisled inTabl. I I

T.bk l.t Ial fo. noFqdtunn. Dlo6.d.l |!GdE ddf@

ryj4!

zt

sgcnoN-?

MAPPINGDISEASIE GENES

BYLINKAGE ANALYSIS

I' LINX GE ANALYSIS

U.rrs. ,sbai! ir ! ledDjque us.d ro d.Lmjno uE saotic lo.€liot or. dir@cme sd in die .bs€ ol dry otbd irfo ni@ (..&, @ ctrqasic .bdorndtt

@-inh.riud disord.n, god csiidlr. 8c6 or hbd p@tor podud) The 8o.l or

lir*lsp M.l'.ir is lo irldrit a pdicuLr t.3E6r of DNA wli pr&j..lv lroM lstohth.r is i'tEit d by.[ d!a-!f.d.d nabdt of dF tulv but Dl bv ev ortr!tr 6dl6d ddb6. This egndt of DNA is sad lo h. '@-!fiariled" or lo "@_

s.rr!err.'*ih Ihe dis.@ pnaot?. ono ibi $cnol is lod.d il is NM.d rhlt tls

dse grr. ns li. wilti! or h dd p@nnit lo |bd lo.diotr hmbig lE

locato ofd!. dis6o s@e (i e lh. dis@ s* loN) h th€ n6r seD toN{d denli64ns

Th. sqE6 or DNA wilh hDm |o.r'i6lh &€ N.d in U!r.8t $tF! ecrlled pohmrphic ietes or'pobmQhi$d Th. pobftorpnic rwts u$d in

Iinlos. nudi6 e lttic.lt cdidd€n |o be baist difidl6 in DNA $tr vlD

dlmnlv bd{6 mr@l hditiduds sd Fl di.& tutlri@ dmld6 Ths

Doltmllhims Ee tbu{tltl t. hutu €r.ome dd 6 be food htu€ ad cl@ to all

s6 By idslitbs t @inhsn d pobMDhitt! l6tros tddironl pot@rphEtu o

rlF vicinily. dxl 619 tlldniol trosrs 10 scF re LOD eB, 0E dise g4 db. Dld wilhin . dilr€l Eeion' 0& !d bv r.v polvmohic dr6 T1* SqEtc

dilrad of didctl r.grd is ,€sE!d in cM (6riMor9E)

Lorar! dd$is n@us s rel.toNbp ban@ ldi Tso lod on |no 3.m

ckomdft c eid b h. fitred if d* PlFomd o' c6i'a ov6 d@ng m6E

dc nol ep&.re |h.n 6 oi4 $ eourd b. 6pdt'd bv @don s'sF8'id If l*o l@

s6 DhFielt cl@ 1o a.b ods 6 dE se dhn@r|e !E d$v sill otnv mt b'

!.pmt d b ! rd'nbi&ti@ wan ar dioaa dd $6 lht tso l@ 'ill ldrd io t'hh@t d losedld. ft6 @.ns.dl or.ltsl6 of {tiredt dks ot aog @ iho l@o

drtlJ|j@ru 3.sn*d is ldn d !h!pkivD., dd Jl.l6 on dt !.r hqiolvp' e Pa"on ar?a* in pcdig6 ml* epr'I.d tv a c|lgvs

'vdt(Ou, l99l)

Ths Danicule dlel* eidleibd nlh th. dis ondt ditr!' bdwa fdnli6'

rdl€cliIa alclrc hd@ed ty or tEtrt Sadic @nbiEnd 6ds TlE |ats of 'ti'r,*p &Ebns re cton d 6 LOD sG reprenog d! rddiv' lil'[nood dnl 3

dis.s l@B dd a sftlic Detd e gasicdlv linlcd (si$ a @rbintdon fetiot

!ld! g). dha tbo sdaelt 'tlin&.d (O!' l99l ).

lAl narbin tiotr fntidAllel6 of dill@r saE on d! s@ dD'ffimt @.et!ede in propone 10 ttE

dd'liel disas bar6 dan Tltu ra& B .chd ilE lt@$nriin tutd (0). rh.hr.Dcan de pobltilily of a @nbindio .61 Mmi4 bdn6 dE hro loci T$o l@'

@ sid L bc !@i.d! lird.d rtE '@hhcEd@

6tcli@ 6 ld lt& 0.t. This ntdod oa

oul-sis is @tuj *t'a m of dB I6i n . diw kd *hile dE olh. i5 ! DNA tM*ab6.d 6 o @tjltM tobmalin b rh. topdni@ (std6 tn Rd. le96) TIE oli6r

of lnrlge d]ts is 1o eijtEle d€ @t$in id ftut@ an b &3 iro bd86 lso l@

is ts lnm 0 J ,:e . $/hdt!r - otsred ddieo fiun 50',6 @mbit'lIiq 6 nd'licdlv

sisnifidn d D! Tn Muldjo. tunt dErs &@ 0 = 0 ld loo abE\ do* lo

6.rr ods dmueh 0 = 05 tor loci tu lpst (or or dillsdn dmn@6)' !'d b ! iB@of dE sordic ditu q n4 dd'E bdw s4 h.i Thie @ 6t *dl fdsndl

dsl,l6 Ts h.l $oBnr8 lv' 'snbinllr@

c o6ido€d h be I qriMolgm (cM)

@rt @ d. ret t. ur4. &!d a lg|arc dir&e oa I cM Ep'ga o 9 Mb m dF $!vs4.d pbnol dp (Fodi, l99t) Hoas, bd@ tdtDb ctN6 truv @ b@rnbindion fialion mq @l be llla 6 o lddiive disl{E n6D od n6l lh'EtoF

b.lrcfdnEd by!np frdioo inro d4diraE (on' l9llrJ.2 Tb LOD md o.|n.d

M6u'E@t of li.bge 'qdc ouli.g ol @nbind s i' tn' p'd'er6'

homvs il b ofta eI to$ibl. !o @!r, do dt dlt For |xa r..q '1Muolik€lihood dethods tse bo .pplied ro tllow olculdid of dE lil€liM l|lll a g'vd

p.dig suppois dE obsaton ol liit gp uld6 ditfsqn sumpt@ lbou| |n€

@odbin lion filcrion (slt!d@ ed R.rd, 1996). In d6e cd.ulsdoa, @ombin'liot

ad M-@nbilErid tor adr posibL gdtlF e dtolli'd Conpulss @ ulilzdl

for dis- d rlE cd@ltl|os @ quile smDL{ A logdilhm ralio t c€lculated demt€d q

z. Th. @tculaEd sG prcvid. rhe stasth of ddae in f.vot of finrtge

Ir a LOD s€r. cdcultlio4 null hvpolbcit is udi7.d i ' , $e problbiltry otdllo tn

ttE fmily ,'e di* &d n!*d c linLd.d thd.aoF et 3'Cteg,trng ind'p"d-dJ

is 1akn 6 lh. nuffiolot dl lhe pobabihy if dD disw ed $' met€' @ u'li'ked tddEefor€ s€saCanB ina€dod,v n dio in Oe daohin ro' Il d! 8Er'r od rE

dis. sd e utlinl.d, tlF nDmrlIor *ill mt be ste{l{ th& th€ d@mj"lot t'd uE

logqitlh ollhe obbi'ed dio *itl be l* nld or.qud lo 0 Hor€d, slto de Mta&d tlE dis@ EFs &. linled, rh. ruEnr.. *ill be stEL' lhn thc d@nMtot ad E

!3

logsirhm of th. nlio *ill be !ra$r thm 0 A positiw LOD st is e mdiQtDn of

linlr€e. A LOD sp of I or sr&b i.s Edialdlr' @6idd!i p'@f of lintaa. for

Manel'i lraiq $tih ! i.gdlvc se.urporls th. 3b6sE oflinbst, Hlh ! sE or -2

or l6s beins aNids€d proofolno-lin}j€e. (ot( l99l , T@iu3er tld olL l eea)

lJ.t M!ftlpoirt dptlngLirr,g! ady3is o b. mrc poRqtul if ln. d'l| for moE tbd M loo @

m.lyz.d sinolhously Mul|lpoitt trtppin8 is pim.ulet sin rot findi'g tE

.hromsorEl ords of ! s of li.l.d rutlR Tn 6utl sbnihg poitr u trrpptB a

dis6d l@u n b fnd . twopoi.r src ich 3uppons ltLcF b.'w a sp-'lic

mortd rd a dis. locus Usins infomdio frn lddlto"l DNA @k'6 in $e

.eio! s nulapoht eE is .roLr.d b bdd 6lin le th. lo@li@ of di98 c@'

rt,a DNA DotrrDttr - ! i-l r.1 ttL.a. ddtd.For [nrlgE ar,\sis, n is nd6s8v lo e pobmQhic turle6 rnil @ &

smirod fd idsirs ,nn d. di4 l(fu. Tt* e@t. tElt6 rcptsn obsdle

potmrphis *i6h rb poFdrim Ttt &sisnng of potflupnic nE*Gs lE if,gtoved

$irh iE6lE h0lM g.1@ dlrab@ Piio. to 1930 x a lirtEl e@ otSddc nE'rds

trs ddl,rbla Ile irludod blood eruP jtss. dd oib' po&in pdtrtulphis

(coilslly dd B.iru, lgSo) h lgso\ €r'dro 6!gnc ld40r pob@Dhs (Rrl'k)

l@ irmducdt 6 ! w chs ol gotdi tk6. {iid' 6'd wi'tid in dE DNA

sff itelt G Mqdeli{ '!,t6 (B.isor d ar ' 1960) subs'qMlb llllRt (vairb!

nn6s otEdd r.!.s) !.d STRS (srorl lldd r""ts) r@ iddjned Fot mrv rsSTtu pbved lo b. rlE msl ustul cls ot potmtphism

'or sdnic s.@ihs etd fm

Sqdc nEppi4r Th. din adv&46 ol SIRS @ tlE ubiquilo6 pls@ &6 tl€

eqbm, !6 bich d.sE 6r lobtudi$ it dt Fpoliio4 'n |h' srdl 'mun or

DNA dutr d c of,rpdld b RFLPS or vNTRs IrF lhon Edsn Epd d!' kDM 6

si@sddfei soludodad rh. m.ld of saotpnB in lbe r9q' s STR'3 e t'$s

@i.ble rrxld sqEE rEp.ds ntich cdE5l ofdi lll. o' la! Dckc{i'h ftt'ds TrE

dsr qiddy 6.il sflk d.dop€d lor ctFr}lirts re rnc onple CA ad GT lt'ats Tbc CA

@.* e edtab.Iv abdrt! lld a be aodi @ 'tagt @ tldt 3ero kb n h'm

smm tsurrq t! Rad lo96r TF sld rdFuLotd' r46ts e l6s |:ll|)@A bul

have tE .dMlrse oapodlcitrs g@q!6 lhtl d 6id 1o soE

29

CHAPTER-2

MATERIALS

AI\TD

METIIODS

30

To Ffm Bauic [nr.se ad pGirion l clomg ofg@ inrolrcd in ardnoN

4sfutrdioa dE worl pld nDy Bqlidly be divid.d inlo ,r@ phM.

' Clinical Evdudion

. L$odof M*2.I FTELDWOR(

The field wolt involvs:

. tdarilic.rlon oahdilg d€d.d f&riti6

. ErollrEn orid€,rin d fmilid d @lldion of blmd spt62.r.r |ddffeno. oftanlt.fidd f.nii€

FmilE *ilh ira or moro !f*td idividurls wqe jdarifi.d thmDgh iotd LiDj

dd i6lilul6 of sp-i.l eduq!6 &on dif.rs citi6 in pdtisld rldividurts n@6k d lo conplae a bnef hjsbry fom in UrdD lo &quiE prctimi,ary intomalion abour

dE lrmb6 ol terl8 .fal..t indiJdurtj i! lh. dadcd fdily, barinS ts/d5pffi or oorer disas, posrd addr4, lrd conrld relephore.@bg

1lJ E m|||Et oa lddri|t.d tuitid Dd @tb.tio! of bt..d udrt6r'eld Irip6 wd $€d ro mll |h. idalitj.d fuitiB. Munid. amity .@b6

ed .ldds ** ifldi.$d ro 6I*l dcGted infonution !bo,r dis@ hnory i, $.fanily A onprdftrv€ qBiomiE w6 6ttd oni by fhily ndbos ro N {Fnature ol oditory d,sfin rid s ovilol1lmrdt or Sqsdc &d ,'rn@nic or mn

tldtmic Ths h.lp.d b obrdr tonosirg infolMrid:. Ase or ons.i of h@ing impdimt (@gdibl, pretnSult, posttingual)

r &.oa*dtiiler stin o. hoir pisncnldo. Poblm d'r.d b br|!f,E visid! 6roid, tdd,:.rs, hdl &n Dd.l

Iljmonnc.t Any cidoE of inldlioc dis.c tik ngingiG, Ml6, n@p6.

rubdh or q?hoid.

. Hsior' of mtr dr,tr orB rdrl u!Ey.

mlibioridoroloxic dtug usas. (Nanyda cdrd}(in, Sreplo,rro.)A onpdE&rc pedigF *a d6M io Gdllin dE o@guiry rd |n.

.pp&an bod. of inn dt&e of dedEs ir th. a6iv Blood sepl6 wc doM fromthe lfcten a wdl6nomDl i litdu.b ofdE aM y !t r.bted i.diuduats, bs.d on

!hq. w iqgB &d lvailabtlily. Casdl_! l0 r ol voous htood Ns @uered deprm cM or v.ry tlul8 or eldqly subje!3 TrF sanptc w@ laboled ed t pl r 50 nlSlcntin'fd@ tut€ .l@dy mlbinS tm d of 0.5 M EDIA. An anforr.d o@4{ind @|drEd delaLd infomdjon aloul dr prcj..r *s siped by dd lolols

22 CI,IMCALEV I,UATION

Clinj€l l6rng indud.d:

. Audiotopd r€tirB

. Vslrbutd |Bnns

. W'@lo8i.it qei'lrio. aor rtriiris prg@r@2.2.I AUDIOII)GICALTFITING

For Minrlio. ol h@ins lbiliry. Audiom€r.y dld Tlspmomerry rerc

To n@ue hqing. audioheEy w perfoo.{ uing s udDnerq whjd! N6c.libr&ed ro idorry Md manor rhe q?. &d t.rd of udiiory dlstuEion (psin8 udNc*,r.q 1995). Dding dE t6! edds of vjio6 tr.quaj6 (trElrld in tE&) errecd to d i lividual a1 djftut itnGida (@6u.d in daibdsl dd 0E tor61mio!'ry thGhold al {hicb . pffi. pqeivB soud is dotqmined. ThcholdgEbriti€ of nShr rd ldt G rw tr6d.d iddcFnady n Gllrj G @dedm . clun cded e adiog.!\ in siict $€ fi.qleie h Hz @ prolt d on horoorlll&s aid Int@ily in dB on vonicrl si' TlE .udiosrm o,orjd6 a n14 of clasit nCodrrory dF[nuior t@rdile b rlF d.gE oa !4iry inro nitd, edsdq s@ orpr.rouxl (Fg 2.l) (BGds, 2006)

During lhc p6.nl sludy, e AMBCO Aodioheld nodel 65oAE md a Sim@sD 70 re u..d lor &diotoaiol Gring

All.ded idivid!.ts indudcd in it. pcar srldy hd <li|I.nd tads ofaldilorvdysfhcriotl .arSins b.l@ mdsdq evde sd pbfoud lev.ts d loud f,equ6ci6250. 5m, 1000, 2o0o, 3000. 6000 &d S0OO ltz. Tn udfd.d individurls hld lr.nngb€lw c2JdB d lh€. nqudi.., v,nicn i. cGid.Ed mfl!.j hdins l6rt

T@ t}?6 ofaldiomdry @@ gaeott perfofr€d:

32

. PoE to!€ rir colducnotr rdlom.rry GTA)ln Fft b. .n @ndEtjo .udiorn.ty, drpho6 m !s.d lo Drsl s.d

lhough rh. deml d. Th. rtu*Iolds dcpcnd @ rh. 6did@ of d. cxr.ful @ @d,niddl. .u, dd inF d (K.t, 2002),

1l& syrnboh usd for rish ud l.n 6 PrA meauMenls on audiogm m "o'md'X Esp4aiwly. TIE ilEF of $c cw. is. lrr..s of dE 6qlErct sitivity ofhod rhc niddle d dd d. illF d ( BFndd. 2006) (Fi& 2l I. aom mdmtton .dior.rry (BC)

aone sducion audimelry is p.rlomed to dhtineuish snFn.eu6l rm6

codaliv. n@irg lN. sdri i. Fenr.d di61ry ro ft w s thmd r vib'ator

*trich is ph.€d on rhc ak!U, usn lly lll. m61oid bon 6 fNha4 $c byp.rsins $€

ex&mll dd middl€ d. lf bore onducrion tlwsholds of h6ine e b.tr.r $m PIA,

tnis sueg.sk a onducrivc haine loss (Knrz, 2002) (Fig. 2.2).

a

!-i:':

:

;

Ft, rr (a'n r.rErdtldd dh'ry Drfrtu

tl

.t=i

E{

3i ?t.5s:!

an;"

SdF.lneurrl lqrh: hs Ml!.d ho.irc t6Fi!- r,2 srrDr. ridi'rro (kn od idr4 tF d^dh4 Dlrudbr

To€v6lut fu*li@ing of.h. niddte d, lh. njfii*s ofth. 6rdM is n*urnby tympeonctry. This 16r Dbtides q@rir.live inaomrtion Nbout th. DEsnce ot nuid

in the niddle qr (oiith n.dh), n.gotivc middte €.r p6srq ed tual votumc,

di$uprion or rh€ osiclcl' $np.nic ndbmn FrfoErio., od oro$tmsis (Noble,

20or).

ln this 16! . en prb. is liddt placed h the exLmt 6 cadl, A@usiic .ne.6ris lEMilrol inr6 lhe Mlt by ! snd stinuts 8.n@rq. pcitive m{r neslrivcpE$ds c als i.r.doced inb rh€ .a c.nrl by a vrouum pump. Thc movcme ofrrnpdnic memb@. in Gspons lo pq@ cfidg.s k m6lred by rh! rlnFnome.rnd @td.d s a r)npdosm (Noble 2001).

lf fluid is F!$l i th. niddlc @, lh€ Dmp.nic ndbdE *i d vihdL

34

properly ari a nar lm will app.d oo $e qmpeog'.n Ia lhde is beho or loser

prdur of ai. h rh. niddl. @, dF lFp-o3m wil show . shiR in lim polirion

(Ciffi ed Sade" 2003)

2J2 v6rihr..t. rtu!TIE rglibulr stsrdl! .Nislir8 ol ilF llricle sule rd 6E s@<jrcula

4!L, ollroL dioriir of rh. body. v.6dbda lAtrB c psfonr!.d ro damiE 0E

frlxddiig ad ideeily of dE v.sjbllr epun6 Tm teds ollmdy pdfo !d lo

.vd@ rbe vaibdr fidid e t||o R.nbq8 161 rd d. Tad@ €Bt |6r

ln dris 16l ltre psrjd n dd. ro iad nill *ith 66 closd md bolh acr

rouchi,g togdns. |f th3 poiol! h.v. vdribulr d'€6erio4 rhet @ rcr @j.t!inbdae dd dEy bein 10 swly or fall Tl'is hqtd b@e lor.l sLbili0 is

dinldn€d by irpus lrom lh@ selory systnsr vdlihul&, vision md prcDrio€ption lf0r@ r ! nild lsiM in lh€ vBribuld or propnoeplion slslm, tlc psdrl ce@nFblL ty visud Dpul. wid' cl6.d .y6, hosM, 6u.l inpur is r@ov.d ediElbiliry b@n6 apparqtl (SlunFfdd, 2m r ).

TIE Eian s.n 16l ir a 16r in *ni.n d'. p!i.l i, 6t d io rdr i. ! shich lnE

,nh hn hntds.fl..b€d wilb dE body irI rc ofdE b$I tod buding dE lel oad.t@t f@t d ch na If rh.E E ,y peblo fidr rh. v6libule sr5id! rlE F@ m.!

tul sdk prcpsty (Rubin dr al, 1996)

12J Oitri.d .lsmt or R.tlnltl Pl8nrn|orRdidirts pi€l@lN (RP) i. I prog6liv. d.S$Erion of r.ti@ Ttre Dr.limrry

slmprom includ€ 16 of Dqipls.l risio and nigh blindB. h Lds sl!S6 il m' t<!d

lo lold blindrs (Hanong .r ar., 2m6) G*dlt lM 16ls @ p€rromEd ro diosnos. Rp,

2.23.r Fod|@ly or ODN|irrt.ottAr oDhrbrl@!. G 6.d !o ceia |hc tury ponio. ordE q. ($e flrtq)

stid imludg 6€ djrr optc drsc d@i4 d brood y6dr Eio.lo MiElioa rh.pup is dil €d 6ing t fd droF ol Tblioid. 0 5% - I % G,ly'lrieo ror ohtibi'rslh. b61vi4 iBi{t rb. .y! (Nov.r, l 93 l ).

Opldhainmpy of ltE raio in idiv uds wilh RP Bab l[. pr6oe ofd@F of bl&l de|Ml or Grir{ .idn.d EliDl vNL! lN ol d&t pig@lopilh.lim (RlE) ad Dano. ofrhe opdc nd. (fis. 2.3)

l5

rEu Lrd.irrrlr*-

2l3l Eb.rDF|hoam T.t (iRC)ft! eRC pDrid6 d o6j6tiE ma@ ofod.!d oF nlrdd @ tn.

rclira. Dudng th. t*t lnc r.lin.l 6Fff. to a srinulG of lidl ir n*Bd silg.cdBl .Lct!d. &d NUFd d*rod4 tbcd d dre *ir 'tud ln..r!. A 06s[ of tidnis shou io rhc ldidr dd rh. .locr!d6 edd 6. rdiEt poi@ti.l5, snict &wlop a rEfloG. b tn 0.{L Ttir &ssdc Flc.dc n En|| fd et.'41b..wt.rtidy of dind diF ih $d B c@ 6 Dd dtlrDtby .!d R.dniri! ftgIFnE23 LtXOn ',TORYWOtrX

23J DNI artudon filo hlood F!pL.T!. coll*r.d blood s&pl6 r@ bPt n@n .ihe at -70oC fd 2G3o oin d !r -

2eC a6ldg-ran srongc unil d. @t:lrFElar orDNA cdr-rid. cddic DNA

lg .!6!dcd t6 di b&'od opL. folloln! t m{.guic o.t d b 6tr'ditrs ..p.

. Blo.d mple lw 6$qt ro lr$ dF tld blood etL.

. Bl@d spl6 w.E w.sh.d wiln oi 35 nl ofTE b{fi.r (10 nM Tris Hct, 2 nMEDT

' pH 8.0). Supk3 l@ 6tdn4e.l d 3()OO rro fd 20 Din dd rtF

sllqulinr sa.ti{,,!.d io rah dr th. Its.d RBCi W8nna wB r.Dat d

ri.€ !o fdrriG dn ri tEC Flla bm. trEof hdrogbtnr. DiSrda of F!ei6 ir 6G FU.rs of WBC ru did od !t .ddhg OJ rlg of

pFi.ile K .1og win 200 ld of l0% SDS b ln. DE$@ of 6 nt TNE tof.r(l0 hM Tri HCI, 2 nrM EDTA. 40 nM N{l).

. Thl supl6 eep bn ovmghl in s mub3Iilg sh.l.r d a l€np6al@ of l?'C

,i r sp€.d of25o ryn. Por.i^ @c pEipild€d by !r'di4 I r of $Frsdlrncd Ndl, follostd try

visorcN shltine.d ch inS d i@ for 15 ninut6 b6foE @nritusalron ar 3000

rpn for 20 minul6

. Th. rupM E dirftcd ro mlk SEiliilF lllon tub. lrd DN s6aold€d n@ |h. supmd&t by rdding a e{ud volure of isoDropsol

. TrE DNA p€nd 6 MlEd win 7()% €nEd !d lloNd ro dry. Th6 dded DNA

pdl€. E disr$d n t@ TE bufa (10 nM Tft HcL o l ord Ema pH 3 0) ddltd.d d ?ot in . sds bd fo @ hod io indilll. rt tlmi.ile nud6

tt, QrDrifiorio oaDNA

Tqo rFlho& *.6 u.d for quotific.rion ofDNA

23.2,1 Otliel d6ity MrlllEb (S0croDhotomt..y)

DNA cll|@rlri6 r@ ..I@Lr!d cing . dilutjd of t/100 h . qllft @!tneql t|Ering dE otrir.l dcity (OD) d My€lagdE of 260 m dd 230 m ir .sp€cr@photoneler Th. ..rio orlh€ t*o Rrlines v6 c.ldl.led b 6rm[l. lhe puriry olDNA. OD260:OD230 = 2 0, indiclld I p@ DNA splq rtile ! ndo 16 !@ 2 O

indiclle prd€ir 6|1hjrdj@ b DNA snpre (ct&I. t9951 T1E mdion ofDNA 6 olcd,Nred froh 0E OD y.le ains rh. aomd. shom in t bl€ 2. L

TrbLl.t C.lorrrid. tor.h. dd.ndd ot caork DNA

a

6

aE!6

.E

23Jl Aa.l* !d .LtErhoc{t dd-rtiorh lhis D€Ibo4 DNA M strirDd wih rb. torer inidot liIs dy! .llidiuh

bbnjd. dye ad d4fopho€€d @ r 0.3% aA@F ad .toe widr o hDM eun of !DNA sund&d Tne !!l ws Min d D ler w lishl. dd lh. nor.q@ of lhe t6lDNA rr risur'Iy @rlprbd b hoM st trdid DNA Tt Mounr ofn@tgq@ is

ptoponidd ro lh. mat of .@lcic ed This mdn d aros qudilcirc 6 "dl a a

qu.,xir.ljv. didid or DNA a rh DNA ntdin d .tE CFI L . 60di@ of is@lolt Ei8l4 &d rhis |!. d.sE ro *ni:h n |@iEd irrlcl dui'lg sloEa. rd

2Jg Wo.tltra DNA dhddDNA diluri@ w. rEn. h bw TE Bullq (10 nM lrb HCI pH 8.0, 0.1 mM

EDTA) Worlllg o'gnldoN w€e t pt r 25 ne4! ed 75 ne/$l lor siirl. mlq rdnullipla PCR !,plrddioq r6Daniv.ly (l!bk 2. I ).

2.'.' Prtt nito. ot|&.d r!tr.. DNA drraTo .!ry ou lidrge rdFis i! tdili6 .fi.ded eiri ardilory dy.rurdio[ o e6'

*!ll Ela pld6 nq B d6igFd, aigir8 i'dividu.l DNA 3 to . spei6c rdtSubr.quqIty, s rtr6L pbL andnina . DNA diluti@ of dn irnividld d .@eamdon of 25841 (for singl6 nEkd dpMdion) or 50ry/,! (aot nuhjpld PCR

dplifi.nio.) *a mrlq R.pli@ ol thi! Bio plar. r@ md€ by ! dlp.Nitrs 2pt

dilution i. .rd! *€ll oalaid wid l0 d of mineGl oil

2Jra UrL.F ..rrynr fo. Elortqt !*ltrdtudi. |@liE dalhd. to.iTh. s.r..sl @lkd tuil-! re eEt d io d.& fd li*e. |o paiocb

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ed dcl?, 0.3 uniE of Taq polt@e, o.5Fl ol lox PCR r@lio. bufet (750 nnt KCl,

loo mM Tds llcl pHr3.l, 2s mM Mscl, dd t 0 ln ovstty ol nieEl oil

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mF.lins tdnp.ralu. of 54"C !d d alsion lor 2 min !1 65'C w* N.d (Fi8. 26)

fk 26rltrqdbepn 'b

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dilldet dy6 Mo poole<l toe.dF in a 9i3 edl poolnB pkr' strg 12 clpillar,

rtuiilron! Sltep For 0F lclotuwd. sda 24 d rcR poducl of eldr p@l (b'Y

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dtd o 2 pl of @ oflh. idd$l si4 dtntd. Rot' (c950o ABI) Lz'q TAI|RA'

(Peiin Elm) wd tdd.<t to ilE p@led ni\tuA Th' slpl6 mrc ddtsoEd d e5'c

tor 5 tuu16 tono*6d by quicl chllling on & for 5 nifli6 b'fdt lmns d dE ABr

Piisn 3l0o or 3?30 C6.1ic aMb62J.? utod.a.a ftrtgor !@irttrn!

Tlt @oLd 9cR lDDlioE ld .ubj.ded to elodLd so$lt?iog n dla tl6-!.oiltdy aBl PNsMo 3l0o or r 43 opilLrv 3?3o Gai'ic AIdvd lnrondlon

aboll 6..h sdq i.cludi.g 6le nme, smple @. d'€ tnd inMtl siz' sLodard w6

d.r.d in dE Gc)6@ eftwe !o idatry dF l@ Mbd &d @laL or dh

AulotDr.d [uo@t g@otvD'is aollos lhc pridipl' ol sd el*ltoplr6! I e

*na dE d.re ltbel.n DNA frcrFls del'<'!bo@ tmush rb€ polv@ (POP'4n')

dq m 6.pard.d Mrdins ro &oir siz At lowd od ofrb' capillds ds dy€ l'b'l€d

ficrMb ps rhrouS. rcam whe€ . 16g b@n contnuouly scs the cap,IeH

TIF le a.jr6 dr tl@r6c@t d)6 rr|rd.d lo dE DNA tteM6 ltd dE dn lrSbr

al a !pai6. mrcloE$ for adr d'€. A st6to8rah o[.d! !d 3+rd6 lh. l'8hts

e&rdi.e to Mrdogh dus .l fou lr!6 of ll@6cqn disim d he dde16d s'lh

Np6ofdE16 wih lh. h.lp of.ld. @ll.ci@ sn*.tc dF I'Cht intaEin6 e6ll€.red dd !to'€d a .ldri@l 3i9'ds (l* 4,r | 997I

Auiomrd dlde dia'lFr E Ffod'.d by Ca6d an ld. en*@ Eite

rlE &foruLd lm6@ d€tedion drrlilly of the AaI solaic dt ltd to si& ad

q@di.re DNA nlgrEa. Th. c'Jis of dlt 6p@rEr e dnpbd a ! reclrlcL{t

sd idge tlE d*fopkoem. CnDlyF tl.? !d CffEppd' v40 sn*e(Applied Bidrsieiro) weF u$d to aotlya de C.n66 dtlt Tt€e dElrsis pogsireoil GsFa fi16 dd @rqr ddt itlo I |0tliqti6 @rE C@q?i* dune

imlude lbe @lor, larrL fnetBrs st idedi&r'g labds, qurdnadve d!4 spleinfoiDlim &n @mrHE (Fig 2.?) TIE st lytb8 €d's @ tGfef,ld ro d!!3p@d!h€.€ lo. ilploryp. .rd sl.tis.{ lnts

FLlt a nr6! tk!t!..'F, dold ll[ cdtF/ YI' ftrR" -D;;-Etrei..ri- '.u.Lr b v rb.'*do'..*)Fd

6e:d*,d-nbd'rdEkqF-(oq.tng r. r * l *to. t an .nwr.r 'n bqtu br .ru -J"lL.k*d|.i..-!y'tr*

5l

2J, tlrplotlF u.ly,ti!Th. s€ts or s@q/p€d !!€16 M6.rD,lsed @ddDg ro lh. ptrFicd na d a

.hre't@@ ro e€L h.plol'?6. ll.plo$T. rdj4nr 6 itrdic& rlE idEilepm.fr of s.cr.ening alld6. f ol Lst dre pobrDobic @t6 dtI s€ lulhido@live o the amiv ed lo.!t6d in dF lirk!€€ irr@al sltow hono2.ygosiq in dF

afi4rod irdividu.ls of ! aedt rtp f4it s cdidad ro be lint.d !o rhd DFtrt

239 D.o o.rrbrdd .rd.r.trt ubr M.6A lll@ n a dini-prcsm

'nich asul6 r rdi6 of 6mads in ompuicr

lesule. (wodn .pdebn..du/pqvw.bu). TIE Mim$R Ex..t bs.d M $.8{atuXy dcrdor.d by da Bioi.fotruj6 rr! a,r dp CEMB ro td, E orgDin'E r*t&ulpfg rli. eao9rirB .t!! of lEdil'y dig€e. ro e tt€ nle pbste,{tiff€Ent .sl si€ll qo made as., D!1! Sh€t Reg6 Sh@1, B6ic Infomdion Sh€!ed Cod. Sher Dif.6n ltfu @Dd5 e tu on d.i! sbel for d{f@r Dodutg(Mtsq olding codnB flbgdc)

Th. dala sb€€t is th€ prinD.y d€ld into dtd rhe OrDqlrrg dsri of i'djviduob

Msr@!d@udt, inrsBof sizoldLl6.Tt .dditi@didon'rid.ddcdlorhi3srE iEldcd: Pld lD. nr.rr6 Mc rup posirio4 h .lrt, tabdnB Oq alde sn&s. (ASR) irdiudud tt@ &d ils lD froo lhe p.djsr.q di!@ sl.'rul, lnd relri@.Met u wm U5&{ 6lumwi!., *tril. individu.ls *.8 @g.d hol'lnlolt Tso@lum wG signd Dc i'dividurt foi th6 rlo .[d6 oa6.b @t6 (Fis 2 3]

To M a nodule o c panicde ddq ! spsinc mnb6 of6ll@ dd os wasreed i. lhe ruEs sh6r

23$ M-D .Fnti...l oE!.atTh. D.a slEa !n 6. R&86 $-r I 6 . b&Ue !o M dilfcti{ snNe

modul6. Th. cscado ol e.do6 b M de nllms i.ctldesr clict "Tools , o. rhe Mftubs, &lcl Mcq and rho Mtru (AleF3). a *indow wirh rE lid of m.dur6IoFd, th Eleedt rFdul. E !d..t d !d RD @dMrl rE siE. TrE doi.pr6.du@ is degicleit b.lor h FS 2.t,

52

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162.rrd|EbIn.Ia.rd!i.''.i.

Th. d.sisnd ExEl ntu Fovi& nrc dyMnic noduhs for noiDot.tim ofd.6. A dc$ndion of*h noduL t d folloB:. P.Frr.s.: This mdul. is B.d fq ofimarid of inhdit re p.ndn by compeins

thc !lLl6 of siblinss *itn FEn6. Thc M of thc .lkte or.U individuts rhd hardc Me p.@ll slbuld nol bG mE rhe 4, lf dy d.ri.tid Eeedins inh.rn !ep.nd isfond inrn &r!,Eld! ell is tighlish.n in Ed.

. Colorttr8: This noduk hilhliehs rhe imozygoB .tt.tcs by chsein8 rh€ir

b6ckgNnd 6ld. Fd ! sird. n.rtd, th. s @te is signcd lo s. $r ofElu6.IfoNtidon s.r of homozy8o6 .tlctes vs pEsnr in r d!t'*! ditr@to16 e signcd io rhsn.

. codlng: This nodul. @bzs nl $. lttcl* of ! mtk r dd signs th.n !nundic c.<t . lt thar ga.6rB ! sp.e ".o&" shct hrving rI rhis infom.lioninhct rs in qEir.l ddr sh..! .@p1$n @h dt.k is Epr@d by i13 nul8ic

t3

. Filing: This mdule omdld !E allelic dar! for r Civd sl ofM!6 in de fom of

.o@@!ed .lld6 IrE ourput of dE '!dub is d ep&dro drr. $c{ te.d B6i.lnto'",licn porulald ! 6llm lrlded _drd6" Oda @ll|m ofdis $ci enled in hdudly @rdiry ro the inlomlio. conained m tbe p.diere Tne E6ic

nao sld is firoE !s.d to rul pr. tl. for LOD sor. dlcuistoa. c6t Po. Tlis tuduL picls rhe dlrr fi@ "Bai rrfo" !b..r d<l otuE6 it in s

spsific paneh romjMded by LNT.AGE $nw., &d eve in ! rdlfo'lddfile Nili ! !E d16io rhis pre f e is s.i a sEins Doht ror cslculrrins l-oD

23.10 r,oD S&n .dolid.ELOD scor6 Eplgd rh. dsl emcidn $dislicil mdd lor evdolns

t€digl* f6' linllae io Md'ddid frib (Monoti. 1996) LOD soE ws. coLulored

Ning FASTLINK (v4.rp), r DOs bG€d $ft*e prla!. (Scn f6. 19 is.i!11*€rdl. 1994). Two poir rd n bpoint IOD @6 8@ cdcohl€d slh MLINK d:d

ll}I(MAI p.og'e 6pdrv.ly (Twillgs ud O( !99a) For cdculario. purDos,

dsn6 "a $l- c e uroAomal lEsiv. lroil wilh @frplel. poa@4, dd@nbi..lion 0quai6 in nd6 !d f.rD.l6 rw sun d .qual Cdi. diltclg6 ldd€d lrom lh€ M.Bhn h nulM sadc mtp (*w.mdhm.d or3/e-di6) Dd!

$a ldded to rh€ cdoiat4 soN{e by follo$ing fr16:

. PnD flLE: h it ! sinplc el.?.d frlc $tidr duiE Dfotnttio. Ee?tdna lmibsirwor.. sfr*ri.. n$4 lrd s of i.dividuls, dorB wrh rhar eqo5Tic dd!

. PED IILE: In rhs 6le inlonndioD lbour lhe looDs ud @'MBri@6 ,rMrlce

n dE hn y is 6Ga{. TIE l@ps & bD\E ein 0E hdt of. pio8m .med

MAKEPED lo radd th. linlrg. dcurdim ls n o!rc. TIE plogm htts 3

double mtry ol ln* individuds ton Bh@ $€ lmps wq€ brota &d Bule h a

. D TIILE: This il. is flEd. rilhdElElp oIPREPLINK pog.dr! Dd @ntai.s rhe

all.le lrequdq, of erch @rt€. ortz.d TIE ftequ@a oa STR MLs ,lld6link€d b DFN loi wq. 61itr'!I€d b,v gft9ti4 lh. eaonic DNA tror 100

@.ld€d Pltisr.ni subjdls. For lhe nErd *t* ctual Fequnci6 Nerc .ol

dirlded, th. .ndc n quas6 *@ @Fidad equrl @rdirB b d. d.I! of

fdDl_v, o. lo .nel6 *tth €qurl frequdf,f of o.l wc amed lo trdG lolll sd

2J.l0.l LIOD Scoa ddt @tp{tThe Link4e Cotol Progre (LCP) &16 .ped ad dd fi16 a in ul fi16 sd

emsa16 o _p.din bar.h frle" whidr o aeulion sasar6 ! nb sith 0E detelt n@'rinal out- A FAM2PD PROORAM T6!ds lllo FiMl out 61. ed livs aat fleoaIOD $06 in noraai 61. aomat

8.lr DNA q6dnl for m|lttion.l D.lttitDNA s€quadng \6 6.d to a.dyrc lhe nuclarid. bs6 (A T. C, d'd C) in a

DNA nieMt {ad) lo i& 4' ndrid i ll, ssE tuire ddnory d}rf@cri@

Tl! trlsl n€? in thjs pro6 w io mplit d! t 'sn

*m tuouci PcR singsp€ilidlly d6'si€d pri.6 (Prii..3 $.bsite Na.s..mb.aorc/csi-butpnm3 w..Bi) fi. PCR producr !@ Irbclcd trith nu@rf dt6 ad*ibed a!ove?. You .!m1 rEl_\.r r.diolaHLd podsll on m ABI PRISM

irolru@! ,iich dsds nmr@t l.b.ls Morc lio orc pims D8n *s B.d to

mplity mlliple dl}li@N lo sllow s.quociiS of longd 4mAn dlomlr€d ABI PBISMe 3l0o Ca€tic Ardya *6 B.d ro lb\lr llE

labeled bes in aor did.Mt colo6 for .{ T, c dd C using B'g Ove Tmdalor

Chonis.,- 0lcjn6 a al, I {r3) Th. ABI PruSMo 3 I oo Cdelic And)zer luclioN de

s@ "!y

ror bo$ seqwins ed C@@ oaltsis .e, elaropnoretc sePadion ed

soed..l d.l4lion of dy. lald€d DNA fE3mnb

2J.ll.r E!o. iddinedo.PCR ra.liN r@ Ddfom.d rn 50 .s of l@91& DNA in 2s d r*don

mi{ur. The PcR @liotr rinN 6 lrla i. T.bl€ 2 5 To @nnm l'l. mptficdon

&rd puiry. 5 d oflh. PCR produd ws ddPa{ m t I 5% .esoe s.l

T!bl. !! Ro.don oit.urc aor dpllftcldo. of PCR Fdgflnb

JlsL4rlJrp.dn. eP)

'rox Pl:]lMqam lni t'it L eH 3 a. tu 'N(cL r!, d r,3clr.d r%rtib)

55

23.11: f,XOSAPTdtodtTlE eplifi.d p.oduct @ 0p t 3I€d widr . njxt@ of @Dud6dl ed

slrinp .ll,line pn6pbot& (SAP) b Move uiMrFnred nud@rid6 &doliaM&l6rid6 G.bl€ 2 6). Th. ninuE E itruhsrqt d 37'c ror oE hou. |||o at

80"C &r I5 mi. lo i@rva,!e he er4des lnd l6lly lr 25oC tor 30 di..

23.tl3 S.qnddn! n*dotrTo rh. EXO-SAI lrd.d 15 jj ldim hixr[., .quat votlm of dHrO *r

add.d ro dilure 6. $lr @l68!rior in dc sqt6. Clrl. s.qrry:ns witn torq!.d &|d

revw pdns ws Derfomed s@d?t ly 6113 lh. fouowinS rs.lion nirarre (Trble

2.?). Th. PCR prc8m for r.qE ng r...ri@ is giva in ri& 2.9.

T.bl 2n Ra.rir drtuF for Ex(lsAP ru@nt

T.bL 2.7 Ra.riotr dttuE for rqb.i4 qdio.

. 5r dirdio hdtr (Tro4t 4n Dll pH 3 r. MscI to nMr

ry.ae r4h.rl* tu:F-.t |gfusitrrad bFdu ryv{ytutu rtuR

23.ll.a h0.riag. pmrlo.l for oqldlr! o. Ga.ltc Atrdr*.S€qE,g .!.cic c@ sd up in % $dl MFTADp PrCR pld6 (-43I) &d

pFjDn r.d Ni.3 .d@1. r 9 0 !r of 95% dol dn 1.0 d of drl o E .dd.d io rhe

l0 pl *q@ds rc!.don b rEle th. nnd mslrnion of erheol up lo 60i J%. The

tla16 w@ sal€d wilh 3M S@lcleduiDd foil l!p€, vone{ nixed. &d l.n .r .oon

tdnF.nft fd 20 niol6 fq pEiDirdio. of lh..d6d.d poduds An wds rLphc ra @dnrgid .t !250 rDn for 306i. !r 4"C &n so!@r'll a di.dtu ur\

inv.ni'A the pL& @ ! p!p6 lord Th. D.ll.ls *@ w&nd wilh 150 d of 70% edaml

ad da d dded Th. &i.d p€nds @E dislved b 12 d ol deidirld Hj-Dift

Ftuil6 (aBl). Smd6 w ddurd I 95'c for t rin folloN€d b! qu* .nixing

b pltin8 @ i@ b.f@ lo.diis o rh. Aal PFJSr"f 3loo G.6ic Astz.23.rrl A.dylir of DNA S.qudd

Nt6 6!d rua rh. CsElic &!tzq B€d rhe AaI PFISM slqMcng &Ebsis

$n*c v6im 37 ro sba |n. s9l6 ad E!6 d6! o Bd*|. fom. TIE

s€qEs w rha @d MDdV 6 Clmru sowe vl.45 Th€s.qudE wiho@np.r.d to Dom.l $qu.re br 6iru .id{ Nuclolidduclodde BLAST (blatr) or

BLAST 2 Sequ@ (2.2, | 0) @ dE NCBI w€b.

SLAST (Baic Locd ligmaa S.eI Tool) i! t lmib of sd' pro3t@

siih ft d6igd.d io aplo6 3n lt. djLbL d.rlbe {Jd . qsy prDrd o. DNA

sqoeE (AlEdul e, al , l99o). BLAST 2 S.qua6, '3

. Dw BLAST-bBd t@l Qhich

is le tin+cmdin!. Ir is us€d for rlisd.r ont t"! homolo8oN s.q66 or p.ol.itu

or Ml&lid6 (Tloevt !n Mrdd4 199) B<{h d* pbgtM w us.d tom d.NCBI wb3i!. (hq7/*w.ncbidfrrihSovbld,,b'2s.q/*tlac.gr). I!. culli'rsalignma e p.6ald in bolll grehicll Md a1fom. Any por6ni.l nufiio. in lhe

DNA s.quoce M @Iinn d bys€qu*ing bolh sre lDd Dtw sIreds.

51

CHAPTER-3

RESULTS

AND

DISCUSSION

5a

SECfION-I

LII\KAGE ANALYSIS

FORREPORTED

AUTOSOMAL RECESSIVE DEATNESS

(DFNB)LOCL

PROIIrcUE

lin*!3c @lFi! h^ pr@.d ro b3 u .ft6iiw ndod to idarit w lmi in ld8.osE€u6u fmili6. Ii ha als h.lpld prcvide *do@ lor Inr.g. to the Eported

intsvals h smdr foln1 *tnch wuld od4ie t too !tuI !o suppon sis!i[6tlinbg€ on th€ir oM Th6. $nr[ lin*6d tmiliA h.ve ba dd|€mly helpful ro rfiftdc idErvals of r€pon d l@i *{ich s r@ h!. rd ponliool cldig (Ol! t99D.Uirlse ltlrlis I'a b€ thc pnnEry srfiing poid for idanifodon dd potrion lcloniry oa mosr ot lh. 27 lrDM @siv. d*6i6s sqE. Sixts of lh6e ctd.d Ba6hlw b€' ida.in d d!reWh bir,ee &b!is h P.lid&i foili6, dn includ.: G/4,IDFNAT||MIE lDr.JtB6\ ItK:] ()ma7/1t, TMPRSS3 (pr43et0t CDH23

lDhNR12r, UShtC \DFT$ t), poEts (DrNB2t\ CLDNtt (DFNB29\ DSRPJ

@Fta3t, t;scN lDrla3q urx lDrNB3 N)x (DtNt24 TNoAp (DFNA2uiAR 'EL2D (DFNB49\I.RTOMT \DnB63) si IMH9 (D|ND66/6, Nvet al.,2@21

Kwitudal, mo2,Borket al,2tfrlr Atured erd,2002iAhned e, al 2003btWil@x.? dr. 2mf ; coffh e, af 2mE Ne et al, 2004; Alrcd a al.,2(n1\xts.t ar.. 2(a14Rihddin dr ,r, 2c\06q Riaddi et 4t , 2ou6b, tnn n et al ,2003: shnbbn ,r ,1.

-rln! l'ge otibulion of rb. P.l6tdi populdid io ou ud*lttrdiis orhd.drtary d.,Ins giv6 slroe dido@ for de high deg@ ofgdedc nelebsad! ordae's latsq'€s ri Et6 i r idal popuLdd to sid h rh€ iddiEcnid of dEldse Nnbr ofnllm deanB sos vhi.h r@in ro be nlpped &d ids i6.d

Tr|. pl6at dudy b.gh *idr drbs6 t6iiry for lu*rse lo cpon d dadr6lei, an h fuili6 lnr€d b krm lei M hdptut in !€ducirs dE raoned lintls.d.flols &d lha .uli4 n @e ro frrd dD ulhsm sG I w6 ale aihed .ttlnms mw .frl dld6 oa Eponcd gn6 *tich nBy h.tp ro 6rruisr CtuqTeph-ot!. oftlalio.r dd rhu b€lp dddLed nnElion l mdhri.m 6f disee

Fi.dns noE f@ili6 lirled to . Epon.d lru is d$ n tptut i. poputdioD

l*li. sMi6 ro 6dne th6 Elatjve prcvdm of drdat l@i nil my evatu.ltylElp in dE Db8osi5 .d DEEnih of r$Disio of 6. jdqti6€d @.

(h. or rhe most inporld purpos or rdlins for tin*rge lo epon d too 6 ro

f,, tlE u, irl€d p.dis6. rvlid @ b€ lna b. lubjcLd !o i lFro@wid. li,Ls6s ir odc b 6nd mvd l@i This will 6fits ab,@ o( hD*t.dsr of saEri6 ofd.!6r* ed pmde ben€r iEish inb rh. pl!^iolos/ of hesng pro€s

Dui.s rt p|Ed srdy, 6oy a.mdi6 wirh rhd d mE .fded i.dividurtM. mlled 6:on ditr€t e6 ot P*isftL Liirrge aubsis fo. E ortd l6i ws

6icd out on rMry five fanili6 wnn dsdild audnory dsr@cl'on. Four fml'6@€ linLd ro Fpo@d lei iftludin9pY\DF3a3 dd p,/'DF b6 b DtilEl. PKDF I toi ta

,/)F/vr7l/l &d PKDF.|33 io DF A29. Mndionrl o.Dsis of SL2d,4J g* s6pe.fonnd for PKDFI46 ud a p@ios! rooned nulllon (c 716T>4) ss lodd The( ,artlJ aft B s€q@ed in fM y PKDF,133 nd . nov€l mut tio (c.331GT) B

TM otlE fMili6, PKDFI043 ud PKDFllo4, .tso gaw lu os€ b Mt4ndlinB rh. DlivrT2 loc6. PKDFI I 04 h€Ip6d ro Etim uE tint'3€ iwad ot DrNa72.ttlTL PKDF 1043 ra hdpin in a$pinS of . @vel l@, ms d6isnden DiMarlTINXAGf, TO DNVA'

PKDFI46, a R.Jpul tuit hwrB aou alldld ildi,iduds in lh@@Bosui@B sibships, w6 sto .d fbn R.$dDindi (Fis 3.1) The &do@rrtpbfil. ot.f6ld individurts V:9 ed V:t I shoqed bjtdLEl &dilory drsrun ljo ofvlryin€ sdily in bolt s (Frc a.2). pbBicd .@jElio or dri*l€d ndivid!,t@al.d rc aoiter or dr.* olhds}npl(j6

'sidld wirh &diloav dljtuctjon shdeindividu.ls v:r .'d v:2 l@,Ettt.d&ted bul hld @ adirory d€ficn.tlotu4t6iry .r@pirg db*td ld.Sp .o ni@s.tdtire nEn€s D7S2420. D7S2tt56dd D7S2459 al d!.oll@m ?q3l (Fie. 3 t) Th6. @r* 4omps a.egion ll)erc.'r€ ldi fo. Pqdr€d stidoe ar|d m-sytdrchio Drrv84 oEnrp. A, L\.8 w6 .otnnory of soiter in |n. d.3f individuab of 6€ rdity, gis sug86t! nurarj@ sr rh.DFxr,, loos ca4 only noFs_,lmni da6ls i! rhis reila a nsDh tsepoolLOD @E (ze) oa r.49 B obbin€d ror lhe ror.r D7s2420 O re.sl cM) .l@nb|di@ tr.aior 0= o

S.q@ .rlbsis or p€,r'.r, coding qo6 ot sa(:26a, 8dq heboEd in rtF,txr4 inEral, Dv6ted. Dpon d hoDozlgo6 subsrjtulio, (c.7r6T>A) in qon 6 ofrlF .ffed€d individllh (F,s. 3.3) This ojssee @brion €u& n ..pt@man or

iT* "*" (v) or Berh 6idu. ot peturk voki. *irtr sD.nic &id (D)(p V239D) in dE rtrird ardattull don la ot p.,1drtn (Fie j.4)

B'

:

?:'iiiFi;€i3Seqti&1

:t5iE"

:;F:+trEF:&<t::iiisqr6!rFla3sic

EE!.ii-

*E

!Itr1l

b

i-r

I

-I

II

-II -

-I

IrI

II

62

oaa"i?i4uat

:-t&

t!:5

l"

nar.rP.Eld.|r6*dhr.!e!uo.b..l'..tdhd|ddtdrxDrl.6ari|bd bdh'rutv:t (r.!ar.r).'t mb Fr..d ddr r ftd.r*-.Ft...r.b'|{|.L(rc! 1.'.')ffa lreb F||ri dd-b h *L pd..rd rdb!b b dr l||h -r, .o" d .x.

''Db d'qd b n tI-dn4.Hrd.|'. |it drdd-E ori.rdtu-bn .hlnn|.|d_

tt, rso6t .ri-lro.dd.n a scir., dr&rE .. r.tddhftlfu|o.Pnn.6l'h.d.ftd.cn.D^E.|d.s||p'ra9Ddn|.

IGYA'D)

oaaa?trrrta

Fr....r,.i.t tE-'r.rcnd-,Lr!t,r.r*.

LINX GE II' DT,V'IPINPKDF:'I3

rxD683, .lar. MdiM tdit s mu.d toD Surlr Siidh TlE ADitn d Oirld.ff.s.d iditidu.b in te Scl.(rio4 t.rSh irdividut.nibu. ar

d,. ri@ oI colLdi@ Oig 3.5) Phricd 4eiraid of ln. .ldr .f.d.d i.dividud5

doa€d Dtq@ of Soiia {idivno,|| DlO, V:5, V:8 d V:10) slin. soi!. $ Dtdid.ar in 0E youl8 .tr r.d irdiidud! of 8-r.rbn vr (.96 5-12 t€s} T!.&ditfii. pb6b of.&d.d idivtu.L V:10d Vl:5 slrrid !'drrd redr|r &ed d.&s h bo|b s 1Fi9 1.6). Hllorrp. ldydr $owtd lid.g! !o

DFNi4PN hil.q.Dr3z.2o,W S,J6 rd D?S2459 .r dFtr@D 7q3 | (Faq. 3.l)A di'lM rbtd.r LOD !oor! (Zn) of 5,28 E obtdd 6. th. 6la DlS2459

(l 19.81 cM) ! t8ltin lid Adio. 0 = o

I

-

--

EiEiEE

et€:!.I!=5+.:-9

iE4i

ilqE&l

;!i-lET

EF

.E

it

ET

iFge

rE

--

--

-

--

-

I

--

!.o9!lo

-

t.

:.

.r.r"c.rp.tccc p"cdd*tdfdd.dI

q

e;

9

{

rt,i6 I\E h ir dd-.d.cflr Atr&r r.ddM v:ro (.c.31rxr) I

^trnd bdv|'lu|| r'l:l (8 lr

'x- rFb dEr-. n rL rtr..a !n s, nt .rr'.t

Lr{taaca To DFNtTn 1

H(DF 0'Feily PKDFtlo?, a sndl c@t'sui@a ADit wa col*r.d nos Mnli,

Pujib r|d bdo'E d lo Enr GL T|l f.dv i4lu.t6 tdr df4r.d individu.ls in |so

looDs .dd rLE ofrhcn bdo.siig to on loop w olc(i.d (ti& 3 7) all da d*i!dindiidulk (V:2, v:3 od V:4) d!o*d pDlouDd IE iig lN n! bolh d (udiqm ot

idividun V:3 srbm in Fis- 3-8) b mil6Ld 6 odludiLrv stnplom. Duiie

li.lde€ dly:i H.plot?. ,or d''e hi.G.&l!1. ffiire 'udo r!9S1337,

Dqsll24 rd D9Stl76 ErsLd |t!r dl D. .f.d.d @n!6 E@ honD4lod fqd6€ @dcrs *lil. tlE 6md i.diriluds l@ lEl4o44o6. ,45 dF d*6oonps the @iv. dstB l@ DFNaT/I I a &bM.9qI3'21, Ih. fimlv

N miidtd [r(t io b. IhLd iol8b lid4. dt& E .tt $atsE TIE

nwimd L,oD sF (zE) of 2.l7 ws oblarEd tor de @16 Dqsl 124 (67.39 cM)

rd D9S 1376 (6?.39 cM) ar @nbincion fr.tdon 0 = 0

PloFltgt

HtH gi IF93.7 POFrlo'r Pdtn lfu b Drnrzlrr otr. brhoF rE h|r,r|hd,

Ifr .yrM nF*n dlid-r rb .!&r tfrxnc ud.. rtL.ndddr r..d odtu b.M rntt- de|.n oredv'.

i||il||ti

trt.i"

rrr"ddf*f,ct {rddle.d.cdfdddB

:"f.

3.

tl3r ^, ^.dq

ot.dk'qbdnndr|rryi(+.oy-')a hdd sdlcnn ndng.r d.rftdd r nddor v:3 .t .KDfuo (4. r!Fr) rrdh. rr!ftoda'..|od i. 6. dar. n. m i, EFndy. I dF Ldr* r+r.9odradElot..|8.||dd

67

LfilKAEE'fO DFN'29/CLDN I 1

PxDF,ltS

Fhily PKDF|88 6 as@in d fron Goj6r hnj.b ud b.loqs b Mlghrr

caE. Tnis 6nily hld fu alf@r€d individ@ls in two N8dnms lo.pc (rE. 3.9),

all .fci.d sbjFti disllay.d bileol prdiryull hding 16 rirh m 3i8rs of ntnr

blindn $, eoiEr, b.lre prc,btm q oda cli.iol $nmlili6 @ssFllting *ith

rDdnory dystunction. $e oudimeLic .v.lunion of th. afTect d indiridulls Iv:4 tdIv:6 indi6&d s6 ro FDfsid dcsE orlri.3 la (FE" 3,l0). an r gcndypin8 30

sIR mdteE ar 29 dciftEs lci (Tablc 2.2), ft. dafiEs pi'eiottpe sgrttri.g in rll.rd.d irdividuh snw.d cvi{kE of li.},*! b Dtvr2, m.tt6 D2ls20?8 .nd

D2lsl252 (Fie. 3.9). A mdimm M poinr LOD s.c o12.07 q6 obloin€d for

micFstellire m*er Itl Sl252 (35.45 cM) rt Mbin rid li.clion 0 = 0.

D66s !r the DF,vr29 le6 h.s bco shoM 10 be assi.r.d eirh muldions in

rhc CLDNI 4 eefr (wi 6r .t d!., 2001). DNA tcqEE lElysis of tE Cu)Nl1 g6c

EvaLd ! honozrSous sobstitltion c.23lc>T in lhc ain8L coding.xon I (Fig 3.ll)

Thi rdioBly unnF.r.d nissae nohrior tgh. in d mim eA $bdidio or

%lii. (V) for hidrly @een ahino (a) (pA9av) Oig. I 12) in 0'e s€@d

rds.mbte dotuin ofrh. c/6dtFl, Dotein.

PloF48a

ll llFt, !, t'rsttrat anr.G br..rr- rd brmtri:ID{,1 Dr... rr0rvF e d

|l'}.||'.|M:Fh.lFI*e|din|r.irrbFfu(Lbd.Mmcfu.ll[.bndldiga

j:E ll

, a e +, d.f f,ttdt

c

FEtl0 ^.a.

PD b d! cfr.nr rdlq'td or.rtu hdtu N:. (|3. eF ) d lvs (r n rlB) , l|otli r.ni rilful nr br,*-d d..tu c tdrrr r. --l r-.i rtr r *, (... tFtl _a

-d rx'Dr.r drF. - t rl| -d s-, ird'{. +||.r lrdd

-tFrsd-brr.!n-rrrr.d

E

:Jf;"

t,.

i-

!"

.rrtr{'dddddtf

d4f.l{cCl/dd

6'

E

rEl!|f cr.r-9l -'il b ctNrlo|r.-.Er.nirrrl.E{d^olvr.i'or.i.t[-.'.ftd..ffirdict ar rrqtc.ltreTsldfi.. 'rdn,t,trodd d{.F^'i|V. C, CrEftsEn or. i.r|l4d -'r.r hdrnrd.

I

t

ia

i

ii

;

i;

'

r|3ar o!d.r. cm.!E rro'rr ffido.oft. r.a ft luE

SECTION-2

MAPPING OF THE NEW

AUTOSOMAL RECESSIVE NON.SYNDROMIC

DEAFNESS LOCUS I'FNBTI

AT CHROMOSOME 19p133

A lag. D@b. of dd6!d lsi &.1 g@ 6 $iI op.or.d to b. m!rp.d. Ou

hb de dso eptdrs |hi! @dioq !c.e tuE rh 50% of rh. d..f ftni[.t

'nh 'dlinted to lh. Eporr.d lei ud, tc!for., r'ry nenor mvd lod &d 9e.5,

h'cro uE€9orr.d i' 6. irdory ofle .L6* eG Tlo P.&d-i p.rdridt ta $oh 0o be *.@nFry

'!.ftr| fo. otliq DfNB bd

b . .en to ihi& @El crd of t|-c'.\ w udaro.t socrid.li&9. s d tm b'il-r |id ditl4nd D Ii.r.C. b rb ldo* .L6... lod. On

of |no (P(Dfi35) iildt n4.d to h.dir. . dd itav.r @ .hotted l9pl3.3(DFlVt7, id .nd ddiiod sr(|y .d nltd E6jEH! H!€d lo idrdry . mFlr@r!, D*rl€iCn r.dDF t 3,l.

3.1 REPORTING OF Dfl|rTri A FORECAST FOR ,r|/r8]?KDf,'iI6

TIE fmily PKDF335 wa d@ll.d 106 Sidrol Oujab). IXis a@ib belo.ss lo

lh€ Cqle cde ed th. Puj.bi elhni. group. A p.disrs M dr.M rne. m@4ngnultple r@iv ddbd. Th. p.drg@ @Bisls or tou g.Elaios, includins sm

'.<livduds (lv:2-lv:3, in lwo l@pd (Fi8. 3.13) dhibidng hil.lrat cons@id audilory

d,snDcdon. Tne p.ililrc rd.ded erosotrd @6sirc nod. or ohoiil{e silh rwo

mmau|l|Fus nfrrg6

Cloiol hinoris ol p.nicipdin8 foily ndb.6 w6rc obtdr€d ro .rl€ our

edqd 6vilr)ll@td .!e of lsirs 1o.., Dd Dbdc.l aduditu w uridrtdlo vqi4/ lhll dad6 wa M{yrxthmic TrF Romb.B sld Tedm sair r6rs w@uled to t6t v6ribula fuFlion ed ol. oul !!y bde€ probl@. The atrELdidividu.b w.a &o r.d.d lor |,t pl6.@ ot soilq, orlfidr@loic dilordeG skirp's@ldi6 $mmulitiA lrd di!b46. btt me of da. alr&ud'rory phdb$!6

Pw roG ludionady for lir drl boc @iduclion M Ddfof,!€d rd dE lfdt d

idivd!.k (IV:a &n W:6) d filqu*i6 .trgita lrcn 250 b 3.000 }lz TtE individud

rv:4 slb*rd *vw ro Fofould ldd ol aditory dJ6iiruio in $. nsh * ehne.nodd. ro 9@ l.d E obsdd in dE Ln d Gis 3. tit^I lidividu,l rv6 h.dtbrlcde lo pbtodd h.&|g ka o dE nght 4, d'il. h dE LE d dje kv.t oalEing16 M s@ (Fig t r4B). a* cdnudid &dionay idri.n d dbl dE enrc ofurtitory dr.nlxris E soricsd. Th. 6dc1.d indisdud t(a shs.d r mm,ledilory phftt?. (ai& 3 l4c)r|.tbrrF rDB o, I(DEli|s .$ thttl1. 6 rrFNRT2

'nE [.r!gc db6is oa fMily PKDF 3J 6ins STR n *6 for rne h'otuDFlva lfti olble 2.2) sho$d tn!1 rho di5!e phmqle w not li.ked lo e of dEprcvioGly rcDoncd l@i. So ! g@r. wid. s *s p*fonEd wid th€ HDIO prElM*6 Initat didde of liok gr lo tk dise pnqbit!. in tdiy pr!DF3t5 16p@vidod by two bfomari@ tulou (D19S209 !d Dl9S2l6) rnich wft homo4losi. ad6l.d indiidu.is rrd h6i.bzysoB in @mal intividuats. Two addilioul nEt*(DI95836 ad Dl9S394) fron d. HDs Pel, s wctt s ctosety sDald @te6 setded

br *lloing 8@@ drrba3cs ld etuD!€d in l6e irLJwl h odq ro @,im dE

lirt g. !n aic' pdiel ad digrl !ou{ri.s flE Sed.d idiridurls (lV:4, tV:J,

lV:6 $d IV:7) init'dry pbvnLd l!. Dronnd boud{ry d BIs Dr9$36 (0 cM. 0 95

Mb) od disr"l bralpoirr d Dr9Sr034 (20 7J cM, 6.06 Mb). HlptotrT. &.b68 (F,s

3 13) B.ded ! €Bie oI homo4lolity of rpp inEtdy 20 75 cM, Iknred by tle

Mle6 Dl9S336 dd Dl9sl03a, lpmin8 r phtic€l di.tde of aboul J. | | Mb on

huB drrcnmm l9pl3 3 (Fig 3. l9) Trlis lirlge ftgion slieh!\ overl.rD.n *nh lha1

d.lird h tuths fDty ir thc bb (P(DFr9l ) sidulIDub ui..3oinS 8@Fwidc$&r *tid st s€d li.r4e ro clF||t3od 190t3.3,13.2 (Air 4./, 2m7). ArDttEfdily, PKDF793, ale poidd didds lor br,ge ir a @gio dal ovdllpp.d dE

@hbi..d ..Ci@ ofPKDF33s od PKDF29I (Ai 4 at.,2oO1). C.mltnjr8 rh. &A offi6. 0r* reili6, n @ pnF..d O.l . $dl @gi@ ofovql4 (1.16 Mb, 0.74 cM)

d.,ic . @ deanrd Iru DF ts7 2 (A^ et al.,2oo1) $iE 3 rgtn ntrqEtoaPlol33s tirtog. bdnd.rtr to d€6Nrf,4r'rrt

AiE th. Dublicdia of tlE DFIVAT.? l@!x .frorE se d.d. lo tudnd r.fiE lhi.linLg. mewl. Nw md6 q@ sde.ted or d6tDed (T!bh 3 6) in th. r.sotutrljr\g lh. ,Fl\47? bMdrjd T1e naf6 ndp€d io mw doM de finfrs.trrldll lo 13.,14 cM (3 13 Mb) rddls dE pdidl bordry r Dl9S8'?3 (6.57 cMl

2.31 Mb) lrl disr.l dd at Dl95549 (20.0 | cM; s.aa Mb) (Fis. 3. | 3) TIE d.r. '!dr!ed

Up ovai.Fpirs r.gi@ b.ls@ dE two fhiI6 (PKDF29| ed PKDFI3J) Epor&d i,,rlvAz b a bt l r.gi@ rp{dla 0 5a Mb.

AltlFugn $e dist l dd prcxim.l bomduis of PKDF335 ai PKDF29I srilt

ovdl.p, lhis sug8eled runb6 dEl$tu ws weeledAlld. fcq*r.y .d.drdd

ln ordd io dlculal€ tOD srcx .llch fi,6oMci6 for .dr ni@er.llit Mts*itlin dF ljr*.g. ituwl w 6rind.d by gtutpi.s 96 @do4t i.l&i!d tuddudividuilt itr lhe Prristai populrrioo. Thir poeiLd t ||6@ of dE .[GtG t qKi6.ludlt pBdrs in the popdnion. Fo. s infodi@ nic,c.!.Iir. rut r, n@ eD. rM, $c or mry dld6 ir I populdid eith v.ryirg li.qEry A5 ! !sr.l tuio,

lh. dtre dld. iiequ.Ey in dE populadd i! lw. IFv€g ndy, n @y b. n@ ln&

TcDoLl LOD *oF dlcdrdo[T@poin LOD sB for |l!e fmily P(DF335 *w c.lcd.rld 6ing MUNK or

th. FASTLINK 6n d{ pur,€! (ScrllId, 1996) Dedr6 G ra.d s o

,4

ibdt!..d|!t-.It dlr. rr..dd. flbDdd, d b di* &r.nqry 9! r r o@1. ndodc n odi'ir. tup.d. rft.d|d b tqdtuedb. IPn|!5 prbd. @ rot bt llD Dn(za) of a.lo ar-rr.eto tdo(Q = o) ri6rld Dl98a2,l Oo97.x) !dDlS,|@.0l.lO(T&tl)

PtoF*45

8€.413 crnrc reDr$ r.ddyF b rorr pxDerB 'hbiDFN,72 kr' ... n rl' b DFtlt t br* h.prdrr6 .E tr&rd FutFt.lr.p'gA.rll.d..hdn|d[|t'ft.srR[rr.EmdMrn|t|ly.sdt.do

Frbrr h aldM.rtu (.M) r$d. d e rdta r6bb.&r hr.dr! dnr.. r!.s.M (-3,!3 Mb) br.

b{H b 6. hdkrdrrlt tv4 rv:i tvr6 Dd tv:?,

I

iI

II

t

I

!

I

I

:

FE

lI

rcaaee84e4r,

\

B

, tP<rtddtd.fd

d.f 4" {'. dr/dd

t"T.

:rar

i.:ito3!

c

t"

t.

FE!r. r ?rn h n r. r... r-r{- r.di|I, rftd. .dndd ry:. r'xotts

r+ ra 'ED)

id.a m r F*i &i- b.t fir -r A.dq|I d.ltad brridrr:. t$ rr r.'r |r'q d4 b dr.d td4 b tr .r. d.ni d

c^ld|.'[d.Dldr.dr]bd^rncd[t'. t.t. n ]!!) ,o" rd {x" .yrnor El'td .1, .od*{d nd6m.F.dre,i.r..d6.l'q..ddy'sF!.|.9d

'lF..ben.hIdri*j

l7

rrir. '.r.

ricrori r,oD *6 l0r dMn re br.d dtr.E h ||lrv rnBs

73

3.2 MAPPTNG OF NEW DEAFNf,SS LOCUS 'FIVB'I

PKDF'O'8

Fdily PKDFI043. a lmly oa M.lit lirage 6 idedind !i!m Jalnia.PEjab, id h.rt e6 d*le.l $!j.ds @l of *nicn firc s.E imlud.d in dF srd): Tbe

p.dge (Fig 3.l5) shos [d6 cld d!&rrlhiy hn .l ol dE 'rEir3!.

*@ *irbir

Th..ldcG !@ qu6ddEd ddir w deimin€d td rn lllitory dy:tuErion in

lhe add€d individu.ls m org6lrl TiE af6red nenb6 w.B ptDEicdty qmined

to q.lud. dy aviME d,l c.e of darB Tald crir .rd Rombqg l6rs [@Frfqn d lo idqdi6/ w r6ribu|J d:/dul|im nE.f€d.d ildiridu.h N:3 &d Iv;9v@ 3l$ i.nd rr th. pl€@ of Rainiis pisEiN or orh€r q! daerd6. The

sfdLtd individuds re slso .lEt d for otho @mDn smolom as!@irred Nirh

sy.d6mc ce of ddilory dl4tulrlio. A3 rc afoadirory d.ld! B* foud. drhM4 lo$ in th. lmny I @6iderd lo be non-Erdromi. The pdisre srructure

3'lo ifllic{tld ,€i* rFde ofidqile ol dafB in dE fMilv

Audiom.tri. i6ting ol !dd.d nxlitdub lV{, rv:g rlt tV: lO 6 pqfonned

ro t|sss 0E l.r€l ofrudi(ny djdnlEdon. Atl th. irdjyiduds C&*!d nnil& &dioldicpolilr, wilh hild to se@ hsi4 los al @md-h@iig frequdi. rn s€@ loprofoud.l hiSh fr.q@ci6 (6000"8000 Hz) (Fig. 3.16) Tne ddioSrms ww clejrly

d*dnguiihlrl. lrcm thoe ,.viild wlh prcfo@d h@dg Io$.ril.t r.l:tr1ol PXDFroa{ rd rtttra of 6 h.D Djc]vrt

Th. lin*€. !Dt^G in rdily PKDFlo43 B pafomed ritn ihe nhrr6d@Epaia dE egio of frrrgc on clotu$E l9pt3 3 drlr B d.tired ir fdilPKDFJ35. Tnir et only $ow€d Ulrte to dE reeioA br.t o trlp.d lo ne* dodtlp DFNB?2 r.gjoq sd e r€d in rh. napDins of a E dodB t*6, dsienaftdDFNDAI nfi Aor.l DtNBal l@w is bouded by @k€6 Dr 9S8Ztt (5.57 .M. 2.J I Mb)ad Dl9Sr, (l8.ll cn14 69 Mb) ddimidrB { ll.?3 cM (2.33 Mb) lin*!s. Eeron on

dmmo$ru l rp | 3.3 This regtor acld6 mt only dD reDon d Dr. rz, intqwi blld$ dcludd d. r'lblc l,inlrS. i,rdrl ot t tsmly PKIn29t qoflr! h DFNB72 (Ajne, aa, 20(r). Thi! qclGion lbdlf@ ali|! |||. rlgio of .l|trl|l@@ | 9 sid.d sirtr

79

er.3omrl MsJ, mnic da&6! into iwo difr@l l@i, e{d hdbonB ! g@ ilvoh.njn uDrory dlafidtd (ria 3.I9)

Tt -rlFis or Irr!8. dL of bnit PXDFIoa8 CN ! p|wrl c|!eE .IDr9S$3 i. daf ildividud lV:2, *iich d.6c lh. pmxiDt bdDdsy for DFMAI .

$nic d. dinrl bo'rdrr/ a .Ld4d by . 6rdl idirind IL7 c,no dDq .|@dtdnr i 6. neta Drgs,l rti.t, h.e.q qEd rt dird tdd.. ofDfrvrsl (F'g 3.15) taD i@F qlod{i8 riditr rh.lilbge dsnl ir PXDFloa8

podtFd. dim lFrrt'r lrD s! (Zoa) of 3.5e i .@ditriid fidio (0

= 0) *itb 6t- Dr9659l (9.34 .M) ( T.6L 3,2)

80

PtoFloat

tI

II

.r r.r3 elbt rr brroF . hrt rKoft... .,r. r*r.. .d r.*rrr. dd re,errr. DNd. !F.rF x r|rrgt!Hy.Fd.r'ldlh....b.'[

1.M) .r.r dr |-. r& (Mb) u L..d . D rd! & d ir r..trn rr..M (-2r Mb) Hrai Ll.mt ft' Dm.,

d.'|'d|ndP,!d.rd|d|lidnl'EFd'd''

.tt"eelleaS

otaatllltlt

ooa4iPrlrrCC

4tc"eeilt88

I

D

:

a

IaI

I

t.

lr9"T"r'

n]rr r" ht rc.ar c.|r|- Ldiid rv:..Pmn.. {.. r. r-., .rra { r d..- b,t r- h rr. |tr *rrd..n..jrd.gr|r.|ry,(r. 12 r.n).rr|. ie.r { - r-d r,t b 5 h 5 c^i..r , .idd ddd lvn C.r 16 r.rr) i,! -d .,rff -d ..&r . r*-a r-4 r- b i.r ..d |.n 4'tr.d'nt D

^.ciD r rfrd D:? (r, 16 Fd 5E -Edr..t,.or -..x' rrr-rir-d bt rr.r rd |.. -, ir..rHr.

32

Tlb& 3-a l\l!-lelrt I-oD hG fol.hMod. 19 mrla6 ib fmtly PKDlloaS

z;

3l

3.3 REFINEMENT OF 'f,V'72

BOUNDARIES

Fuilt PKDF I 104 a @ll6Ld fron Lodltrrq Punjd ed b.lonsed to Qu6li-Hrdni 6r. I'e p.digE sh.B $o co@usiB6 nq\s6 lalrine in rhc@ngdrrl daf.hildro nr two l@ps (Fig L l?).

TIE .loi6l birory of tt'. f.rib w @89r.\ ud r @lg& ol s'mp{oE in

diferd! d6f&'d mndly hqi.g nirvilud! nE clinN-.lLsls r@ p.rfod€d for {rindividudr snovirB rulilory lbrcnbdili6 Tne individuals v:4, Vs dd v:7 {.F6t8ar.l dr4 silf,. pblound ld.l ol&dib'y d)€fDEf@ (F,r; 3.13). lrdtvidu.lt

Vr3 &d V:6 rbo $drtd I dcd pl@ttp. $i.n, e.d6g lo infdrrid porid.d by

dder! G not @gdid. Th. individud V:3 had &quitud de tuil anB $ifsins fom

|€led ad w& also .qdt @dod wilh sleler.l shnondirie. Boih th€ pdiat3 w@

cliti.dry Mi'.d dd flun E foun iD 6.n ci iidicli4 wa odi bedit *ni:his ! g*ral as or .oc&rditiry d668. So dr6. individuds w csideGd

eodictlly er.d Ldividu.l V:7 m dwrf .nd congot l Fofoddly d@f Individud

Iv:3 sa dtul dd sirhour ey ba 8 tobLd. aldDlgh sbe brd etrlQsy. Anough

rporndic dis@ gniploB w@ plEar h difisd fdily n@ba3. n@ of d6e $6@{€r€gtlirs wid de!t'6. B€@$ of dis, lhe s€gt srtns d€trK tnt

'r dE &hit

a @aidd.d marrdomiqridt,l. .dti' ot P(DIr roa

Lu*4. @ltsis in fDtly P(DFI loa wih n[II6 0elilg $. rrr-r\472 leBshowed lirk g. b€rvd dE nE*6 Dt9Sl034 (20.75 crv! 6.06 Mb) dd Dl9S39l(23.33 .r,1, 3.s2 Mb) ognpsins ! ioLl F8,@ ol3 03 cM e.a6 Mb) 6 l9p 13 31 3 2

TrE djn l bdndry E ddani.it ht ddl inditdurl V:7 *io disptt€d . p.laEl@iotic @nbiMdor d Dl9S39t Th. poxint boEdary 6 dedi.d wnh rhe ndp ofhalot?. ..dF! of rcmd individual lv:3, {tD @id r t@nbindio dol nd&ng. ldA r€gjd of toDAAGiq d 'ioG.t llir. dwlr D | 9$3a (FiC 3.I 7) A didMtwpo LOD sE (ZN) ol3.l I Ba obninl fdlll.trwtaDl9S934 (23.6? cM) r,r

lMnbin lion frulion 0 = 0 G.bl€ l.l)

llt|;!H$$ !iltlltltilltIti$l$iill&. lllllllii€ftr,r$*!$!!ts:- ff!$ltatlglr

f

giEIg;rrE:

igiligiiEi

ii;5:i!ii:iti 3;icFti

E{iE{;1ii1

iiFIiE|1;ti!;:ri Eii:s:iii

-a

.-.

-

--.

-

-t

-

-

---a

-

8!t

tl

ea.4Jal4,tt tra.t,?ir*tu

I

III

ItE

E

II

i

?Ir

I

o, c r t?l8rt, nat"4ellall

4,1r. ^. rL! - dr a&-..4rr- rd dnd v:.... *!

(t 6 a Fr .|.) a tbtr|.a .4.'l rL.l r.fia a.d- c^.air - -rl r.t rff v:r {r. ra r-.rl D

^rtr,r.t- rv:! (tt x Frl.-i -d bra r - - 'a -.'r.r.r- qt!-r b.. rtl... - -, i.r.dii. 15L.t-{q-rEJ-r.|.atr-a,.da

36

TrbL 33. TbT-p.int I-(tD (oE for.ho@rom 19 mrk B ir fullt PKDrrloa

t fr.d D[Va7? bo..d.rl€TIF lin*rge de f6n fnily PKDF| lo.{ h.lD. .o r6E DIXB7, boirdqi..,

{tich rcw occu bel@ Dl9S 1034 el 20 75 cM ad D I tS39l at 28 83 cM. The lDl€ge

r€ron d.fh€d in PKDFI104 ov€rl.ps dF hr.g€ ini!fl.I of Fpotld D|NB72 fai\PKDF29I (ba€DI9S2I6 d 2O.Ot cM !d Dt9S916lr31.29 cM) bul mlud6 dcr€pod.d oricil lnrrg. inEtul dctuiq DF]vt7? oeN€ Dl9s2r6 ed Dl9slo34)(Ain c, .1 , 2007). This dala sus€lt a rcfid.rnc of lintrse iilerul ol Dr 87, on

dsm@e l?13 3-13.2, disLl ro iE Eoon€d cdric,l in@d, &d sh.dd nos b!e.gniz.d b.r*6 d! trlllm Dl9Sl034 ed Dl9S39l. dDnpars a 3 03 cM

(2.46 Mb) rc8ion (Fic L 19)

I

Tl-IE

t-_tTBt Iot I*l *

T

6 tu*-*re

-xlI

taIE

II*l*

II IENIEI*l,e I

Gl-l

1,IE

IIi

e

Fr&..re sd|dd. oFio d F,rdt F*r.. rd !fu h*. q|I r.r

i.*otEEI|EndbyI|hdch|6rrdGg.l*pddmlr.M.idMb.h ||ro d*] c|s @bolt rpJud [.ht tolrtura drd iy frbd.lel|r.6q|jd.j||dtrddhh'!l.Tt.D.ddc.rfulrrGdarrrddri*DB',,U.rn'l.tn.l.E.k.ndrfud.c}6...d.(DnrxaaDnBlood'!c..4-& b {t ran r-(!hIt)te&ErtntaDfrtzr- ar.d.rcff F..-at d-rr-r- ttu-ut

l,.l S.q@.irg of odidrl€ todTh. Fai@ of dr ,Frvrrl rd r.th.d DENA)2 lei @.in rati a& ld I

ir qrer€d dd tut td r d lcr oe sde al ai of lh* l@i it iNolv€d i. ludibry

dsincion ln m efion 10 ids it dE pdicul& dd66s<@.9 affi d rh6.l@i, .@'did& scs rppoa.,Il *6 adoDbd Tlis b€cFn rilh ! s@ch of tll lnE widtn tlF

diti.d rl€dd bo'rdei6 ustra [F s@rc dt&!s lon UCSC Ct E bosd,Eemble !d NCAI (hr9://gtum |e €du; rw.grsbl.olg: odM rcbi nln.nih8ov) (Fi& 3 20 ed Fia 3 2l ) Th€ lhe fuolids of dr.I 8g1q d.tsD6io in ilE 6, rhc plvg of rF.rou daf mE ddds, !d homlog/ ro

rootud delns 3o6 @! studicd i. delnil Tvo !o141ial @didate s@ sec Ihus

slDn lined in F DINAAI iil@4 IMP?"SSY dtd ,ZRI, 9@ t 4uorc..L Th.

equ*irg prib6 ror de g@ w€ ddsrFd aiig PriE3 eb silc

(M c embmtoE/ca-bi/prind3 m.€) Cloble 3.a dd 3 5)

botmnbture Ptot@e, Senre, (nfi$s9) qa a Bood crni{l8I g@ in fi6

DatBal inLFd Ir ffiirts ol 17 qffi droding. singlcps tlF I 'lmbteOnta\ polyenre Fotu:e-l (P.lWt@J) n^nE rO59 njno eids in ihr6 donoiN:

s.l6e1. S.|@2 &d Sdae3. This pror.in 6 frdvcd h cdlrzins dE tj/drolrsis of

duin p€pud6 (c.l ., al. 2003) &d ts qprded in hmy lissu6 includhg hd...v.

li'q. Iues, hsn od brdn (o*unw et al . 2tto6: cd et al , 2007) 71tzr,5x9 @ ttuns @diddc bele ol lasi iNdv@r or ods rGmrlre pols nudnory dlsfuNnon: TllP!.tsi is iNolv.d n rMei d dddopnd ed muotons r.dis e* l8v. bs repon.d io .e da66s d Dl aSilo (!qt d o1..2$ll,n1l,RJ'Ji h6 b6 repotud ro cle dails i. h!lr@ (Guipp@i er al 200?b)i Mu1ml

tllPRssl ha bF repon d b eNe prcaourd hdi.g l6s in nie (CuiDDoni ., ar.

200?a) Mo6v€r, dE lln €ff of rtlPAtl9 llFs ! hotulog/ *ilh Diroclendn.l

i@r .mb@e 13 a* gA4l13) *hidr b involw{ in lrunw denB dFoni.srdrm (Ro€dr d. 41, 2002)

Frzzyrclard Fot in hMoloAw (FZXI) *a ertE crdt.td. C@ in lhe

DFlr'aal im@al 11 16 I 5 do6 dd -.ods rhe /.irl Dro!.ii! stid ha 4,x omo

-ids. lr as 6xrra.d in vdio6 tsu6 iEluding frc iftr @, ed n involv€d in polan

nodinarid .Dd ubiquia!'rioD 11 rle pl.rs idportdr ble in .dl dlin@ (zhou ,, ,1.

39

2!oat.

Ahhoulh LltPxSt9 !i ,"2x, e@ dNibL qndlhle g@s, lh€ 3equdcin8 of

dl $. codb! qm ofrlF in fmily PKD'335 sho*.d m nur.rio.

UcsC G.roo. Brm..r or E.D|r M.r. 2006 ArsnbbocEEIEEEa-'tu@i;a-.d@mGi.ibfiatlffi.at,i-b EfE iE 2j.3,o!o h'' C€

ra

'ma Dt 'm!|1| D't tul mi @l elNslr 18.14 dEsr fr'l m

I!11

ofll n. Et D'l L?.1

.hl mf al !{rst .6t . .t r !" -l ml nftl !.1 r.l

r!.3, c.f,.errd b r. Dfer r a.n&,vdr|ad!.dbrn u€rcFdlffiixd-^dr)

UCSC Geuome Bro*rer o! E[miD M.r. 2006 Alt€obly

"*EEffi I* o@E@@mot @tr@ponriods.t -rsd&qs laf-1G2.{60.6a3 h. [.fu l

tl

Fealt C*sDdba.ntudrr/9 7zbr4rrrlldbffi byslJea*

T.DL J/r Prlmn !*d aor *{|mht oa l-fP SJ, dolr

3 332

,l{5

3

ll

D-B

l5 566

,2

l.bLl! Prlm6 ur.d forcqdina of Fzxl6d3

2

3

ll

t] l7l299

l5-B

l5-D

Trbl.l.6 \aly ddlgnd ni(tu*ldliL qrlaB |.r ntbdor of Dflva t?

SECTTON..I

DISCUSSION

DISCUSSION

TIE slr&1wl @hplqiry of iE d iurAe*s thlr . lrg. rubs ol gG &iNllrcd h pDviding i|l Eioa 6dio6 Abod 30O hl|@ Doi.in 6di4 gG (t%

or rh. tot l 30,000) @ ! icipd.d b bc rhlved in i|! mcdEis (Fri.dM &dCrimd\ 2003). Urril mw. 133 4toson8l loi hnv. b6! rDpped to r&io6.hotusrd positioE (.nnd publi.hd or Med) rnd 49 g* tarc b6 idd itr.{t

sid dEn csa,iiw muirrioE. Of rhd., 3 | lai e ir$dir.d ir lgiv€ nodc dilc 5?

in domid p.nd! (H6ediry lEin8 hs noD.prsr: htlr ,*ml h& boltS)Rc6ry€ hits @ mE N'@n in inbr€d popddioE lile Prlind *tr@@shsMily poponion is "60% (Hu8in ed Bitd6, 1998) hd lhe r@si! d.do6s

nlt is pr.valal ( |.6 Dd l0o0) (Ehli d, dl , 1993) Bae of $is populidor 3lrElurc)

0r Pltisrri popuhim pl€aa d a..gdoEl s*tic @lE for llE |ilr!e! nuij6of |gAnv+idEiLd di!€ pdierdy da66

rrE lirte. s|u(li6 of fdili6 vith uditory 6|3furtm narc ! rumb6 or

b.rcn|s. TIE pnmc on6 e io hdD in loc.lizins ilE s6d i.volvcd in h@ins dkord.6sd 0E poslio.l cldin3 oaltF loc.liz.d $SFE !o iddiiry th. ddabrC gn6. n is

d$ hdptul in idcnifrc{iq oflhe hbm godic c.|g ir | lDpuliri4 qrdd dy be

tEbtul ro @n@l rl.r tmisid ro Gl gffiai@ br eatdic 6'Elirs ol 0r.fi6r.d f@ni6. Th. linl4e darl n dso h.lpfrd in 6hblishirE smE?cDhoory?.

Tte pl66l nudy E ainEd a ninins dE gqarc bsis ol srdiiory dFluFlio.of diftren i q6ili6 h |h. Palisii popubrim This auld be hdptul @t o'Jy tor

llori&ibg @@ @dive da66 gcr6/ld, hr ako h 6t blislins lhe m!.h eudr-Jt.r stuq}6pnaoty!. orrddioc. To ldi.rc dE obj-tiB or rhe Dc6t study,

Ii0y oE r8Dir@us tuiliB, segr.s.ri.g d€!t6s ri.jl ed ahibni'lg rild. nodd e,

evaq or prcroud dafE w @lbd non ditrqdlr .6 of Pltislar Twory firc

oadE feilid !4 s.ldt d &d subi.d.d ro [nr,s! rdrsis. Fou of dE tdili6*w [nred lo hom danK lci DFNS4/PDS, DFNB?/] I rd DFNB29rcLDNI4

Tm fdilid PKDFl,l6 d PKDF333 slDved li.fae b dD r.gion

@mDAsin3 rh. ovdhppiB loci for ,FXtr, PDS ed ,/,,1, otl ce!€d drc io all.licaidfi of SLC2&11 A@ DtNBa is deEized by mn{ydrcnic tsiv. d.rtie(Li d ar, 1993) *nn ir PDS, daiB i! era.d *ith goils crti.e in rqxtrld

95

sJn&ome (Erq.tl ., d/, 197) dd t/,{ is a Eidrohe signiryine 6lu8cd velibure

lquoduc *id data ,ltut?e (usi r/ al, reeg) Th. dif@ b.iw6 DtNDl

rd PDs ir mt 6dly ridan h tous .f.d.d indiedurL b.o* goita !r@9De tiMnd.ldy padrml a smElt d.vclops aftd tlE rye ol l0 )6 (Radon d ol,2ooo) Ow dl rle sLC26,u turdim .@ul for lpponmdy r0% of hr.djlary

d€an6 in Aen Grt r, aa, 2trB) dd b.i. b@ foEd to b. d. ml 6m ..e oldadr6 in P.Li6i poDlldiol! rEpr*lriu 7 2% of rh. cs (Anrr ., al , 2009]

Th. cli.icd exmirdid of rh€ old6r dd€d iriiidurl in fmih PKDrl,6(aged 23 y6) @e.lcd m $gN or goilq !d lh@roe M.'ndromic d6nr* alinlld to DFxat iD lhh fhny Fmrt PKDF333 is c sydmmic t&nib, wnn evidat

epild ir.lds.trd.d irnitduds !n j! [,led ro Pdnr.d s]ndrcft loc, PDS.

MuLtioEl lrb6b oa PKDF|46 rnal.d ! pHioLdy r.pon€d @|rllM mdrtjon

c.7l6T>A in qd 6 of lLc26,4,t snq R|ncn reuts in & mi.o &id subtlitulio. ol6pelic r, (D) for ! @tEd€d v.b. (v) (p.v39D) (Anw d zl, 2009). TrE djornle of tli pddrh prohnr i, ro trulon iodiE ro dlow FoF ptoddio of lb'mid

homN (Ollm rt al, 2004). ln additor\ this prol€i. is thousnt b sna.l.y rcle itd€ functi@;s of rhe ba.l dd inlmdhlo o.[s oflh€ rr.ia wr@r'rr 1o minrdn rr€

odod.hla poralid (wogajm.r al, 20or) Tbe replstEr or. e.polr oni@

rid si$ r dsr3ed mirc rid is lrdy !o 6@ confonDnon l cbd!96 in dE prorei4

atudns ils turdior e'd ruir€ &dilory d'srhcijd (Pst ,, al, 2003) TlE.udibry

dlsidcrio in ttF !tr*Ld idividurls of PKDFl.t6 i. of e@ 10 Foloud lq€l B|liein P(DF333, h@i.g los is nodcll. to e@. TIE haring lo$ ifl4ilv in

DFNaI|PDS rB b@ t.ponA b vdy ir ints- 6 rdl a irt: f&DiliJ cg Qip€z-BEs 4 at, 1999; Mmudi .r ul, 2000t Mpiol|teh 4 dl.i 2004).

Tl. harloqTs ol one lmly slFraB Drofound hsins lo$, PKFDllo7,

dm6Ir.bd li,l4. b DwrTl// !r c&otrs6ore 9ql3.q2l origiidb rwo l6i,DFNAT d DFNA I | . w6. iddffid s.ffddy (r.h e, al, 1995 -d Son ., ar, 1996

Bp€liv.l') in dE s@ cl[o@eml rcgion. l,ld ths. wqe sboM ro b. lhe lmr(ru sd wse @mbirod d DFNBl/rr l''/s cnq .t al, leeTl DFNBT/II deovsr.p3 tilh DFx,€4 rn bo|h e 6s.d by r!!ni6 ii dE gd g!r, 7rtl. TIE

?l,cl e6. oNisls oa 24 aN cEoda.g th. Itrl pDr.ia stich ba! 6 restrhb@dmt! ttd is dtrs.d in cocll|w hrir ells ad v6libule qd orss (rurim er a|.2002). Kiltjin d, al. 2007 hlv€ r€Dort d d[| ! R34X ruridon in Tm] o@url3 lor I 3%

ofdafnd G in |he Pditei popularon

Tirhr Jumr@ e spQlrlt€d IMb@ prol€iN aoud d d. non tpical rc*ion

of poknd €pnneld ed -dolh.lid elk, rtidr m.i rit ellult poleity b}

etuo ing rh. dimBid of !|mb|e liprds dd Drellic (Frer,dl, 1993) One mlror

E o@ ot liSht jLdt@ pDra6 n dE.rr!d,n fdily fTsnib !d Futu!., 1999) rnid@6isrs oa l? h0lM ac dpr6.d i, diltqd rns6 (Modb ?r 44, 1999) d,,r'/,-l4 h . g* on crro@s@ 21 d.r *a idatned $reuh ! CDNA dd.be s{d! Il@tujtr dE @6 lhd dEode ! Drol{ of 239 ditu 4ids du1 B dvolved in DIta29

d.afB (wil6 "r

z/., 2@t). u lB 2545 % sinnrirf ti'D ottu dadi, tnjtnmb.m, p.nicul{t ck!di,-;, dd @nllire four lremnb@ domna fisuliii sdfuruq lr99). I n loud a1 c.ll jwlioc Dd is m i egrl, nulli-Das lMbme proton

qprs.d in lis, hdr€y &d im I ll'{ontt d at , 1999) l|J @ror rcj. .r rb€ rjst

junim i3 ro pbride elciu indep4krr cdl-t dl !dn6io. M'ttrio6 itrD.n 0F

0bilily oa./ardrr-1, !o lom dghr jun lio6 Nln.h e @dal b tha h.@g pm6s

aw.tratofd 4 ar. 2m5). T1r* nu6ds in clrr.l., (393d€lT, v35D ed Glola)h!rc b6 pEyioGly qon d nd @ pofo@d dabd Tn tEr t*o orrh6. widanifred lom |ne Patisbd populdio. (wilox er dl., 2001. warl6nof6 ei ar, 2005)

'tue phootr€ of Clrrltu' mi@ he ba found io be sinil& ro th€ hl!@pl@rtT., bmg pbfoud hdine 16 *ilh brDI v.dibulr nrdi6 (Ba Youd e,

rh. sequ@ dlFn of de C.r,r,V./4 sft ir fmily P(DF433 r.w.l€d a @v.l

shindon dullliur c 23lc>T. BulritB in e oi6 aid cto€e or ddi* to valhE .lrh. e{q 6idu. (D.AqaVl l6ird h 2r rctre$@ do@in Tne deift d rllsposln@ b hiEl'Iy clr|r@.d re niE ortnolo3!6 (F9.3.12) ad jB sub6tirrion br

vrline ha Eull€d h prcfoun udiory drsfhctio in lh. |!nny PKDF483. Ou sw€y

of t00 6mal P.Lin&i dbmerc ilFrtd m @ulrqB or ed€mErtrin3 |nd |nn L ml . cll|l'lM mrml lobmrDhin *ilhh dE Pllidripopdnion S.rh dniN hd idie N mFpol& dd ntubl m Ei&, h.6ov.line s @E rcn-pohl ud hos ldC.. htdiophoh. sido du The nuLlod prord roybe f.ili'E lo 6ntul rh. l|Id.l didaio ol lipids nd lroliB nor o.ll nmble &dihur r'!y h., involrcd in inpFF ion bd'6 *iid! crlt in fliluE oldvBior of

so@d wav6 nno @e inruls.TIE lise Mbd ol da66s foin6 rlint d io rcpon d loci susFl dp

sjigE ol. R looa4o.i csirl8 danE ir lhd lmni6. ln dds 10 sadr for

d6e two ol ln6e udinled fmilie wd. sd{r.d for . sd@*id. lnrae€ s@

rmily PKDF335, wilh mddlre ro $vac harna imptirnF& shor€d a novd linli!€e

reei@ or 20 75 cM or drerde@ I9plt.3, dqDrt d by DimsddliL dttdDr9S336 (0 cM) !d Dr96l0t4 (20 ?5 cM) Th. dirbl li*4e tordd slb*d r shon

r€sio of orcdar $d $e p@nnd bord.r d.fuEd by mth6 fmny in tnis siud

PKDF291, whjci dirplq€d pofohd lEir! lo$ rd wa sidulrfl@ust 'ddsE

ine 3

g@@sde se PKDF29l db*d lDkg! lo ch|(',rlMre l9pl3.3-13.2 b€rwa t!€

ml6 Dlgs2l6 (20 0l cM)ed Dl9S9l6 (31.29 cM) CombiningdFdalaofth6stso

f,,Dili6, n *r prop.€€d lhd lh. ov.nappins F8ron d.6G lho criliod Uloal of a ftwdei6r* lotu DF?r'r72 nis w tudha.urmlod hy 0E [nr!8. dl1a from @|hE

fdnJy, PKDF793, wilh mod.rde lo sd.re hoiiS inp.itrMt As ! Esull lh€ ditic.r

r€on ol I 16 Mb (0.74.M) bcl^@ dF ru16 0195216 and DI9DSI034 s5Eponed 6 DFrvaz Gis 3.l9)(Ainaa1.,7001).

TrE h.lebEcEiq of g@lt?ic dd pnoot]tic dnl oa dE reili6 r€poned bDwr72 nied a posibilily of loN hddos*iry (An .i ar, 2007i dd C6Iillo ,r ,4,

2oo2. clEt ei al.,2(n5: t1ili et .l , 2005; Shlbbir .r d/ , 2m6). so, .na dE publicdon

orDFrr'a72, morc amiliG ** @llcLd en $EFd for dE DFlvaT2 md iE tla*ing

r.sid\ 'd

B mrl6 w (k'srd 10 ttGF of dE ln'l,e. itLddi Tm fmili€rPKDFT 0r$ ad PKDF I 10.1, slD$ld lirl!8r !o d. clronbdnrl 5.8D.G mEpa.dhy |l'. E otud DtlvrT? foili6, bur.l5o Cro*ld 3 d@ difrcFni.tion in lhen [d!geidd.b rd plmr'?6 PKDf 1043, wnn rdd ro e@ ldihy dlsnadoE dDFdlnr,sF bdw ih. Ntas Dl9S373 (6.57 cM) !!d Dl9SJ I O 3 35 cM). Tbis nor only

dcluded dE "601.

.dticd ht*r.l of Dr,xa72, tut d$ indi.{.d dd de lirtae. rceion

of PKDFIO43 rc quiio disliEl fron d. l!*t€p imdv.l of PKDf29l. IlF 11.73 cM

linlz€F unddr of PKDFI043 ea d6ifn t d a . |B loru for ruroEonal '€dircde.tus, DFlVrsl. br 0E HUCO rcMclaurc omilt€. Tne [n}!e€ .e€ion ofPXDrloa3 ovdllpped with lhc Gaion ir leily PKDf335, rlici Na rlso it6n d wirh

the bdp or.d @lG6 ddfing ..w bodde6 Hrm Dl9s3?3 dd Dl9S54e (2o0r

cM) T1E similai9 of sooqlic d!r. ed Dhdolypic similaty or their audiogmsuggd. lhd bo.h dl60 fdilid @ IinLd 1o th. w loos D'' rr./, dd PKDF335

shourd @l be @6dq!d io suppon Dl,vr7.?

ThE lin*lsc dd! from lmit PKDFIIo4, riich qnibils profou.d danles.

telped b .eim Ih. DF rA7z l@B bo@d&6. The PKDFI104 ljnt4e Fct@ li6b€{ua Dl9s | 034 (20 75 cM) lrd D | 95391 (23.33 cM} This 3.03 cni irr@l orEtr{E

{ih dE linlas. Eeion of dE publBhod tunily PKDF29I. An auirss of dE g@o!?ic

93

ad phaDtlT@ d.ra or dE iwo foili6 3u88r$s rh,r bolh of th@ Ep.gt rh. 5@bc'a wnidr li6 dtrd b rh. ilpon d rXtrT? qiridl idrvC. itF Ef,Fd did@l

irtd.l ofD,lvr72 mw li6 bara d. nr.l4 Dl9sr03a dn Ol9sl9l, 3Ddrnirg.

tord 3.011cM rtunrl o demoem I9pl3 t.lr.2 (lig .l lor

Th. fmry PKDF793, 'tuludd

ir DFND72 p,0q lAk et al . 2ot 7r. ws dtor.Doned b qhibn modsde r,o sqd. dedrs. Although iE disld linhg6 bords

ovotlaps aith the efrn.d DF7iA72 int6val, on th. bais of phtutpe w. 3pe{ht6 lh.t

m oetv. gm 6 D$lv€d a jrrli. DFNAS I fanjll6.

Allhwh v.ryirg deg6 of lEiig lN hs. ba Eport€d to b. crn d by

drlfN r nery g8 ea, (rB2 \Dt,NBtt, sLc26A1 (DmA4t X), TE|A(DltB2D in oTlo (DFNR22) tll ot te e fuypidt hddo8d:@6 re..?@!l eg or@dslIe ro ffi a sdl a e* 10 pbro',n d66B (DqD*nd ol, lgtt, Nqiolrek et al. 2004; Ne.r al, 2003i z@&Doe et a l, 20oz t. fhedrtu.rd of trc lci on chremson. l9 by (E splir orrhe rcponod DrlvrT2 d rh.

bai. ol Be@lt?ic dara or fmilid havi4 *idddy difrs{t udionaric Droild sillndD io 6lrbli$ de s@gt6phdDrlF @trd.nd |o a gans dtdr This sill also

ll.lp in urdfiLrding lte @lols bais of E |.li:lly ilasiLd hdina l@ ofdirf.d

Anc d. t fiGEn of dE tFivtT2 inrdrd en dp |milizdid ol )va8/. rh€

dn gorl uG ro idd'ry dE Ddstin3 cds.rive CF5 in lb6e loo. TIE UCSC gaede

bole s 6.d to iddii all dE eG in lh6. tusnh. Th* @ g* nch '6,

*iO ?6 idafie! ga6 Dl6ml in th. D/,lra/ imonl, stlile 16 o@r i. $c Elired

DFNR72 intwd {FiE 320 dlA 3 2l). A ldgE Mbs of d6e e lpod ddjddBbs@ of drn expr*im in $. il@ a or hmlos/ silh ods dafls .uin€ss. Teo pordti.l @ddde gl* IMI'ktSg tA lzRI i DINtsl i ad *6..sleLd rn s.qEEd. T'Mb@ polas., TXARSS9 E Middld r sr'drg

dldid|. t-.e of qci6 ol o0E lruErbre tor6 7l3 ssr, n Pnttjdrt ?VP&'SJ in th. im s dn O.ir @1. h cuing d.aft6 in @ d mie(Cflippdi a al , 2ooiq s6t.t al., 2o0 r; Cciltori , dr, 2o07b) Th. dp@i,o. of dF

,t7 p@ro. by rh. IZRI gtu * Epon d in rh. ij@ @, dd ib irydvc@i in

pro$in mdi[dtio. dd ubiquiltrulion !!s!sted i @uld he lh. cs4rlive l@ in de

DI:l'tB't i^ad IAN 4 al.,2@3) soq!tuins ofdl lh. dm of lLiPRssg tl ERIin fdit

'KDFJ35 did ml id6dt &y mu|!rid. n'is h6 luh€d ou ddnio b o$a

nronS c&drd'le CE6 in dF r.sio Th6. itulud. dE solule wia (SL(3eA3), H\eE

dobiliy Crcup (// 4t204. n&l jundion prcisnJ (?PJ), UBx don@. ptolan

(DNq etz E trspt -d B'IB dnn irQAfBT'{) TtE tE tggdidlle Er# h the

rdntd D B72 hri.l iEhrde |i. $l!r. @ir (src2rr, d 4Lc25123\

Ctubs3 (CXr3), 8a! tubrti.-a (?urr4. MuolipidiFl (KO!^rr) nb@od poldn

S23 (rRPr28) -d nad.el!'ilfu dbontaaqol4iaM (It RNPA.

TIE idatii.llim ol a uiqw lod! Dfltaal uppon d h! fibiliB sG8t gdirg

md.r.1e ,o sw.6 h.eng impalMl b ! o.tribudon lowed. BLblisllnS lh.

s@tt?cphaoryF @rdiiN ir d66*!s, !d @ dE u,'drbins 3* toGhDwr tlis ei[ b. hdptul d E&!t xli4 rlE D.&is ol !96i@ of difaqnlacl5 of bddir.ly &dil('r dr.6.tliod

t00

CIIAPTEN4

REFRENCES

l0l

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As4 J. ,\., Sb.rlErq G M. .i Corq. D P 0991) Tipli int.3riiy od Ghdi€l t aidioD indd*blnelk Ncum ?. c8J -991

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Bc'!, |{, PdG L. M, Ri:E*lia S., Bd@iG S L. Ann d. Z M- Nq S L Folon@ L.R:Gl'. 4., s. 4 M , snedp.rtv. c. &, $&vG s . Bdl'e t. Ddnullt D - anDed zKb! s N..xirddia v. M, u. x c, ri6i.,\.. ii.zrlda s.. e@4idi€,M.N.Gw E- Li( x 2.. wi!d, G, $'ih R I lt,Gitr'th A J,Sril4E R, Fti,D. TBtvtddt, R J (20or) ulls 3}!tdE lD !n mnsv mi. rdBral diE dar6DrivrlJ m a8.d by .lLli. t'Mios ot $. 6d sdb.iin_lilc ge crlt-'J An J Hu

Bd*h D.. whiiq R L. Stuhid< M and D.*, R W lltrro)Co|fui.. orr srdic liirlcF ra tn

@@uKridior€sr{l.ngrhDdyftrpnkru AnJHun6cE rllla_3rr

C.! S,qxdav,Or4bala,C, tiltolit!C.Pdyml.rhutMDolr?@* b$.ab:l,rtbgem& f.bFrrla! sir Dtd@ tunod frcm . tDtL Fntlaion p'srd @0or) Ptu NdAdd s.i u.s A. lm:glsl'9 lq)

L.ps.l'n C (?&tI E:Dondrtrs tl* onpkrD of rtu hll@ dtgndoftmh ffi dnd ftdr urnem *nn. o@( thu'n( ronr BrM ll 46al _e

&nljberr. D A.illHdqD P.B'!4l\ ^.,

tr/tolnrho, L M.Hou|uM.Xr|h. G FJr, C' irnm^ H Ndd.V.rl4ul'.L.Muthrm,A F,r.mh N I Mu.lle R P il@Are"i tm t

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