Gene mapping and medical genetics - Journal of Medical ... › content › jmedgenet › 24 › 2 › 65.full.pdftein for galactosidase (PPGB)." With the excep-tion of blood group

Gene mapping and medical genetics

Journal of Medical Genetics 1987, 24, 65-78

Human chromosome 22JEAN-CLAUDE KAPLAN*, ALAIN AURIASt, CECILE JULIER*,MARGUERITE PRIEURt, AND MARIE-FRANCE SZAJNERT*From *INSERM U 129, Institut de Pathologie Moleculaire, CHU Cochin, 75014 Paris; and tUA 620 CNRS,Institut Curie, 26 Rue d'Ulm, 75005 Paris, France.

SUMMARY The acrocentric chromosome 22, one of the shortest human chromosomes, carriesabout 52 000 kb of DNA. The short arm is made up essentially of heterochromatin and, as inother acrocentric chromosomes, it contains ribosomal RNA genes. Ten identified genes havebeen assigned to the long arm, of which four have already been cloned and documented (thecluster of lambda immunoglobulin genes, myoglobin, the proto-oncogene c-sis, bcr). In addition,about 10 anonymous DNA segments have been cloned from chromosome 22 specific DNAlibraries. About a dozen diseases, including at least four different malignancies, are related to aninherited or acquired pathology of chromosome 22. They have been characterised at thephenotypic or chromosome level or both. In chronic myelogenous leukaemia, with the Ph'chromosome, and Burkitt's lymphoma, with the t(8;22) variant translocation, the molecularpathology is being studied at the DNA level, bridging for the first time the gap betweencytogenetics and molecular genetics.

Chromosome 22 is interesting for two main reasons:it is short, which facilitates the construction of amolecular map with cloned pieces of DNA, and it isinvolved in a relatively high number of inherited andacquired diseases, in particular malignancies.

Cytogenetics of normal human chromosome 22

Chromosome 22 is one of the shortest humanchromosomes. It contains about 1-8% of the totalhaploid genome, that is, about 52 Mb of DNA,slightly more than chromosome 21. This is five timesless than chromosome 1, the largest of all chromo-somes, and three times less than the X chromosome,the most extensively mapped. Because of its con-densed small size, chromosome 22 lends itself wellto isolation by flow sorting,' especially when thelong arm is shortened by a rearrangement. It has anacrocentric shape with a polymorphic short arm,because of variable amounts of heterochromatin inthe region p1 l-1 ypll 2 and because of the presenceof one or more satellites of various sizes at pter.

Received for publication 1 September 1986.Accepted for publication 3 September 1986.

65

Ribosomal RNA genes are located at p12, as shownby NOR staining. The non-polymorphic long arm ismade of early replicating euchromatin, suggestingthe presence of GC rich DNA and possibly numer-ous 'active' genes. The different banding patternsare defined at three resolution levels in the diagramof ISCN2 (fig 1). In standard conditions the long armappears quite homogeneous and very dark with Rbanding but very pale with Q or G bandingtechniques. Because of this, its integrity is difficultto ascertain with the last two techniques and highresolution banding techniques are necessary toelucidate some rearrangements.

Content of chromosome 22

To date about 25 loci defined by a known gene or agenetic marker have been assigned to this chromo-some (table 1).

NON-CLONED GENES AND LOCIBefore the advent of molecular genetics, few loci hadbeen positively assigned to chromosome 22. Thesewere ribosomal DNA on the short arm3 and fourenzymes on the long arm:mitochondrial aconitase;

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a b

13 1312 12 12

p

11-2 112 11-2

~~~~~11-23112212 121

q 1212123

13-1 13-1

13 13-2 13-2

13-3

22

FIG 1 Diagrammatic representation ofchromnosotne 22according to the ISCN.7 G bantding is obtained at threediff rett levels of definiiotmi of the karvotvpe: (a) 400 bands,(b) 550 bands, (c) 850 batnds.

so-called diaphorase I (DIAI), corresponding tocytochrome b5 reductase; arylsulphatase A (ARSA);and N-acetylgalactosaminidase (NAGA). -11They have been localised by physical regional map-ping, using translocations and somatic hybrids.'2 3Three other loci have been provisionally assigned

to chromosome 22: the antigen of the P blood group(Pl),'4 a surface antigen referred to as S13 but notsubsequently confirmed,' and the protective pro-tein for galactosidase (PPGB). " With the excep-tion of blood group P, assigned to chromosome 22by linkage analysis,'4 these assignments wereobtained by conventional phenotypic studies ofhuman-rodent somatic hybrids, and in some casesregionally assigned by deletion mapping. Morerecently, a-L-iduronidase (ID UA) has beenassigned to chromosome 22, and more precisely tothe region between pter and qll by deletionmapping and gene dosage.

CLONED D)NA SEGMENTS OF CHROMOSOME 22

(TABLE 2)To date only four identified genes have been cloned,

TABLE 1 List of loci (getecs, markers, diseases) oni chrosinosotie 22.

Loca(tio S1 1mbol u(ll/I Iamt ANSOCiated (diNC('oS

p12 R,IXRI Rithosonitil RNAp11 1) FI93S An1onIt11(1ts rcpetitivC familyptcr-ql II)22.S3 AnonVnt10ouIs LilniquLc DNA scgittctitptcr-q 1 (ES C(at eve synrdromc

(tetrasonmv)pter-q1 1 )(, S D)iGcorgc syndrome

(rmonosornr)pter-q II IDL'A ot-L-iduronidlisc l1S. SSq I IC,I I and Itiinoglobiulin light B3 t(8"22) varialnlt

IG(,L.( ci tinN:V lnd C rceonlsq1BC'RI?Brcakpoint CluIstcr rcgion CML t(9,22)q 11 D22.S Anonr mvius utMiqite DNA segitlcintq4 I-qtcr A(:('02 Aconitase (rilitochodtrial)q I11-qtcr )22s4 Anonrrmonis uillquc DNA segtnenicit

)22S5' Anonormiios itiiqmL.c DNA seigmentI)2Sf6 Arionstttious tiliquLc DNA setilcrntD22S7 Aoionsmous uLlimlliuc DNA scgnictitD)22SS AnonVmo0US ,t1tiqLc DNA scgimlciit

q2 ES Fwliitg's sarcomia 1( 11,22)q 2-'qtcr 1)225/; Anonrvnious uniiquec DNA scgi-tcntq12-Ltcr M\ oiN-gohint(eI 2-cqtcr 1'/Pi bloodi grolip atitigetq 2 (q 13 SIS C-NiN proto-ontcogetic

(=1PI)(iF 13 chiaiti)q13-.-.qter NAGA u-N-acetylgalactosaminidaseq 13-3 1-itcr "tRSA Arylsulphatasc A Ml.q 13 1-qtr DIA I- I)iaphorasc (=NADII RCM (types anld 11)

cvtoclhrottic h6 rcluctise

Not issigitedrcgiottallv /'P'Pi Protective protciti for I) galactosidlasc (iS

D22.S2 Antonittous utiiqitLc DNA scgnictitI)22.SIO Aniotvrivttiis illi(iuic DNA scgtilctitD22Z/ Ati01itIItoUts repltitive DNA scgrimit

TPolvmorphic at the genotype levcl. SPuolytniorphic at the phenotypc levcl. 11S=Ilurler's syndrome: SS=Schcic s syndromc Bl1.=13urkitt's lymphomit; CML=chronic myelogenous leukuiemia; ML=rmetachromatic Icueodystrophy; RCM=rccessive cuitgcnital methaemoglohinaemia; GS=galactosialidosis.

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TABLE 2 Cloned DNA segments from chromosome 22.

DNA segments Name of Assignment Known RFLPslocus

Identified genesImmunoglobulin IGLV ql I Manylambda light chainV and C genes IGLC qll EcoRI

'Breakpointcluster gene' BCRI qll

Myoglobin MB ql2-.qter TaqIc-sis(PDGF B) SIS ql2 3-qql3-1 HindIllIa-N-acetylgalacto-

saminidase NAGA q13-.qter

Anonymous DNAsegmentsSingle copy segments D22SI q12- qter TaqI, BgJII

D22S2 ?D22S3 pter-q Il EcoRlD22S4 qll- qterD22S5 qll- qter BamHI, EcoRID22S6 q11- qterD22S7 ql l-,qterD22S9 qll TaqI. MspID22S10 ? Many

Multiple copy segmentschromosome 22 specific D22ZI ? HincII. Pvull

Multiple copy segmentsrepetitive family onseveral chromosomes DNF19S5 pll

coding for (1) the immunoglobulin 'lanibda lightchain components, (2) myoglobin, (3) the proto-oncogene c-sis, and (4) a-N-acetylgalactosaminidase(NAGA). Another gene of unknown function hasbeen discovered in relation to the chromosomelesion of chronic myelogenous leukaemia (CML),the so-called 'breakpoint cluster region' (BCRI).

The immunoglobulin lambda chain cluster (locusIGLV-IGLC)Hieter et al'8 accomplished the first cloning of thegenes coding for the constant region (IGLC). Theyfound that, unlike the single C kappa and C heavychain genes, the IGLC comprised a cluster of atleast six related C lambda genes (numbered kC1 toAC6), each with its associated J segment, andspanning a stretch of about 40 kb. The genes exhibita high degree of homology, about 95% at thenucleotide level with even fewer differences at theamino acid level.19 The protein corresponding tothree of these genes had been distinguished beforein myeloma products as the non-allelic isotypesMcg (XCj), Ke-Oz-(C2), Ke-Oz+ (XC3).'8 Thepeculiar arrangement of the Ig C lambda cluster, inwhich each CX gene is preceded by its own Jsequence, suggests that the CX cluster has evolvedby successive duplication of J-C DNA units.19 Inaddition three lambda-like C genes have recently

been discovered,'9 comprising two new Ck genes,provisionally designated '14-1' and '16-1', and apseudogene "V18-1'. Preliminary results indicatethat these genes are also on chromosome 22 (G FHollis, personal communication) at a still unknowndistance from the XC1-C6 cluster. An interestingmodel of evolution of the XC gene family, stemmingfrom sequence knowledge, has been proposed byChang et al.'9 The kCl-XC6 cluster is polymorphicbecause of a variable degree of repetition of a 5 kbsequence in the 8 kb EcoRI fragment comprisingXC2 and XC3, with allelic RFLPs of 8, 13, 18, and 23kb.2t Hybridisation studies on somatic hybrids anddirect in situ chromosome hybridisation haveassigned IGLC to chromosome 2221 and moreprecisely to the 22qll region.2223

Less is known, in contrast, on the number andorganisation of the lambda V genes. The first cloneobtained was genomic and corresponded to a so farundescribed lambda V region subgroup, calledsubgroup 0.24 It hybridises with a family of about 10cross hybridising genes on chromosome 22 at lowstringency, and only two at high stringency, allmapping proximally to 22qll. 4 Subsequently,cDNA clones for lambda V region sequencescorresponding to subgroups I,25 III,6 and VP17 havebeen obtained. The actual total copy number of Vlambda genes is unknown, but should exceed 20.27 28In situ hybridisation with a kVI cDNA showed thatIGLV, like IGLC, maps at 22qll.29 We still do notknow what the distance is between IGLV andIGLC, but in the light of Burkitt's lymphoma withthe t(8;22) variant translocation, in which chromo-some 22 breaks at 22qll, it can be inferred thatIGLV is proximal to IGLC. 29 30 The involvement ofchromosome 22 in Burkitt's lymphoma will be consi-dered in a later section. Using the genomic probeV4A corresponding to an 8 kb sequence comprisinga kVO gene,24 the IGLV locus was found to behighly polymorphic with at least seven enzymes.3'These RFLPs are compatible with both multiplesingle base variations and rearrangements within anEcoRI 8 kb frame*.

Myoglobin (locus MB)The human myoglobin gene was cloned by Jeffreyset al.33 Its organisation and structure have beenestablished by Weller et a134 and Akaboshi.35 It is asingle gene with three exons and two introns, as inall the members of the globin family, which evolvedfrom ancestral myoglobin by successive duplicationsand transposition to chromosome 16 (a globinfamily) and chromosome 11 (13 globin family). MB is

*Very recently a cluster of three V kappa genes has been unexpectedlylocalised on chromosome 22.32

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distal to a breakpoint at 22qll2 and is therefore inthe 22ql2- qter se ment.3' It exhibits a TaqI RFLPin the first intron.rThe c-sis proto-oncogene (locus SIS)The proto-oncogene c-sis, homologue of the simiansarcoma virus transforming gene v-sis, has beenassigned by molecular hybridisation to chromosome22,36 37 and more precisely by in situ hybridisation to22q13- 1.38 It encodes the B chainprecursor of PDGF(platelet derived growth factor). 4() PDGF consistsof dimers of homologous polypeptide chains,denoted A and B. The gene encoding the A chainwas believed to reside in the vicinity of its Bhomologue. This problem was recently clarified byBetsholtz et al4l who, after cloning and characteris-ing the PDGF A chain gene, found it on chromo-some 7 (7pter-*7q22). Therefore, after duplicationof the ancestral PDGF gene, the A and B chaingenes have acquired different chromosomal loca-tions. The two gene products retain an overallamino acid sequence homology of 40%. 41 A HindIIIRFLP has been found in the intron between exons 3and 4 of c-sis.31

N-acetylgalactosaminidase (locus NA GA)The NAGA locus codes for a lysosomal enzyme,also called a galactosidase B. It maps at22q 12- >qter, and it is not yet related to anydisease. Since a brief abstract on its cloning,42 therehas been no further report on this gene.

The BCR1 locusThis is defined by a 5 8 kb DNA segment ofchromosome 22 which has been cloned at the 22qllbreakpoint of the Ph' chromosome of CML.43 Thissegment is the central part of a 45 kb gene44 that isfused to a truncated c-abl gene from chromosome 9and expressed as a chimeric RNA and protein. Thislocus will be discussed in the CML section.

Anonymous DNA segments of chromosome 22Ten single segments from chromosome 22 have beenisolated (table 2),4-511 most of them from thechromosome 22 specific DNA library (EcoRIcomplete digest) constructed after chromosomesorting by Krumlauf et al.1 Five of them (D22S1, S3, S5, S9, Si1)) have displayed RFLPs (table 2).There are two other chromosome 22 specific DNAlibraries prepared under the auspices of the USNational Laboratory Gene Library Project, oneafter HindIII digestion (M A Van Dilla, LawrenceLivermore National Laboratory, California),the other after EcoRI digestion (L L Deaven,Los Alamos National Laboratory, New Mexico).Since all these chromosome 22 libraries were

obtained after complete digestion, they do notcontain overlapping clones and cannot be used forchromosome walking.

Preliminary linkage map of chromosome 22

We have studied five loci exhibiting RFLPs: IGLC,IGLV, SIS, MB, and D22S1, and two phenotypicmarkers: P1 blood group controversially assigned tochromosome 22'4 1- and DIAl, already con-firmed to be on chromosome 227 8 and for which aquantitative polymorphism has been found inAlgeria. 53 Multilocus linkage analysis54 was per-formed after investigating each marker in pedigreesfrom CEPH (Centre d'Etude des PolymorphismesHumains, J Dausset) and from Algeria. A prelimin-ary linkage map spanning the long arm of chromo-some 22 was obtained, and the maximum likelihoodorder is:

H=(-10 0=0 22 0=0 17(IGLV, IGLC) D22SI MB SIS.5 56This reference map was used to confirm the evi-dence of the localisation of the P1 polymorphiclocus of the P blood group on chromosome 22,which had been previously suggested but contested.The P1 locus lies close to SIS, and the odds of P1being linked to the marker map is 96-5:1 (equivalentof lod score= 1.67). The phenotypically polymorphicDIAl locus was found to have a location score 4 of11-5, corresponding to odds in favour of DIAl beinglinked to the marker map of 3 2x 10"l . although itslocation on the long arm could not be determinedwith accuracy. The physical and linkage maps agreeand a comparison stresses that these two mappingmethods are complementary to each other.

Chromosome 22 and disease

The pathology of chromosome 22 is rich, both at thesomatic and at the constitutional level (table 3).

SOMATIC ABNORMALITIES OF CHROMOSOME 22Several monoclonal malignancies exhibit specificabnormalities of chromosome 22, restricted to thetumour cell clone.

The Philadelphia chromosome (Ph') and CMLThis was the first chromosome marker to bespecifically related to a given human malignancy:chronic myelogenous leukaemia (CML).57 CML is aclonal disorder of a pluripotent stem cell in which90% of the patients have the Ph' marker. It is foundin neutrophils, monocytes, erythroblasts, mega-karyoblasts,58 and sometimes in lymphocytes.5 4'2Classically it corresponds to a t(9;22)(q34;qll2),63and Ph' is the 22q- derivative. In about 5% of cases,

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DOS

Phl

?ES t(llj22)-9_-

MLRCM

(CES)(IDUA) (HS,SS)

Meningioma

FIG 2 Morbid map ofchromosome 22. Diseases are in bold letters. Dotted arrows indicate breakpoints not yetcharacterised at the DNA level. Relevant genes or markers are also indicated. Brackets are used when a locus or a diseasehas not yet been ordered relative to neighbouring markers.

however, there is a different chromosomalrearrangement,6>69 either because the partner ofchromosome 22 is not chromosome 9 but any otherone except the Y chromosome, or because there is acomplex translocation involving more than twochromosomes, always chromosome 22 but not al-ways 9. High resolution studies on prometaphasechromosomes indicated that in the standard Ph' thetranslocation is apparently reciprocal, with break-points occurring precisely at 9q34 1 and22qll-2.71" 71 They also helped to show that somevariant translocations also involve chromosome 9.This was further confirmed by in situ hybridisationwith the c-abl and bcr probes.72 73 The breakpointon chromosome 22 is proximal to the proto-oncogene c-sis.74 75The molecular dissection of the junction between

DNA from chromosome 22 and from chromosome 9on Ph' is a great accomplishment. First it was shownthat the proto-oncogene c-abl, normally locatednear the telomere of chromosome 9, was transposed

onto the 22q-(Ph') derivative,76 and that the break-point mapped in a patient within 14 kb 5' of c-abl.77Then the chimeric DNA fragment was cloned andused as a probe to investigate several Ph' positiveCML patients. The breakpoint was variable on thec-abl side (chromosome 9), whereas it alwaysclustered in a sequence of 5 8 kb on the chromo-some 22 side, called bcr for 'breakpoint clusterregion'.43 bcr was found to be constantly rearrangedin CML patients, suggesting its possible role in thepathogenesis of CML.On the other hand the role of c-abl was suggested

by its amplification in the human Ph' positive K562cell line.7- It was then found that the original bcrsegment comprises four exons from the middle of a45 kb gene with 13 exons.4 This gene itself wascalled 'bcr', and the corresponding locus BCRI.In Ph' the 5' half of bcr is fused tail-to-head (sameorientation) to a variable portion of c-abl.44Remarkably, although the breakpoint is variable onthe c-abl side,44 the resulting chimeric gene is still

q11l

ql12

q 2

q13

D 22S1MBSIS, P1

-131

1331(ARSA)(DIA 1)13qterI

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TABLE 3 Diseases related to chromosome 22.

Disease Ccvtogetietics Aftfected 'evge Locus incolcled DNA

AcquiredCMi. Ph'=t((9,22) bcr BCRI (chrom 22) Chimeric

and c-ubl and ABL (chrom 9) bcrlc-ahl gencAl-L (variants) t(9,22) bbrcakpoint between

IGLC and BC RBurkitt's t(8-22) 1gX IGL(V,C) (chrom 22) lgk juxtaposcdlymphoma C-Mrc MYC (chrom 8) downstrcam c-nyc

Ewing'ssarcoma tIl I,22)

Neuroepithelioma t( 11:22)Neurocndocrinetumour t(t I1;22)

Meningioma* 22 monosomvAcoustic neuroma- ? IGiLC or SIS or D22SI Loss of allele

Constitoution(ult( 11922) rccurrentsyndrome t( I 1:22)

Ring 22 r(22)Cat eyc 2tptcr-l IIsyndrome tri- or tctrasoms

DiGeorgc 2lptcr-q I1syndrome dclctionl

Rccessive congenital NADHI- DIAImethaemoglobinaemia cytochrome

b5 reductascMctachromatic

lcucodystrophv Arylsulphatase A ARSAHurler and

Scheie syndromes(MPS type 1) ct-L-iduronidase IDUA

Galactosialidosis 3i galactosidase- f)P(PBncuramtnidmscprotectivc protein

*Two reports of constitutional aberration. 143 144tOnly one preliminary rcport.'51(

'in frame' and is transcribed into a chimeric mRNAof 8 kb, longer than the normal c-abl mRNA.44 80-83It is ultimately translated into a 210 K abnormalprotein.84 85 This chimeric protein, starting on the Nterminal side with a bcr sequence and ending on theC terminal side with a c-abl sequence, is endowedwith a strong tyrosine kinase activity, contrastingwith the weak kinase activity of the normal c-ablproduct.84 85There are still many unanswered questions re-

garding the pathogenesis and the role of Ph'. Forexample, what is the function of the normal bcrregion, which seems to be a real gene, expressed innormal fibroblasts and encoding a putative proteinof 68 K?44 Why do bcr and c-abl fuse preferentially?What is the metabolic and cellular effect of the fused210 K chimeric protein? Is the gene fusion theprimary cause or a secondary effect of the disease?Interestingly, the variable breakpoint on the c-ablside occurs precisely in the 5' domain of alternativeexon splicing that was recently shown to occur innormal cells.86The joining of bcr and c-abl is highly specific in

CML because (1) it is present in all Ph' positiveCML patients, (2) it is found in CML with complextranslocations,8 '8 and (3) it is sometimes found inPh1 negative CML with normal karyotype9( 91 inwhich the DNA rearrangement is submicroscopic.The Ph' chromosome has also been found in other

malignancies, particularly in ANLL, ALL, orCLL,57 9296 and also in multiple myeloma.97 98 Theavailable data from molecular analysis indicate thatthe breakpoint in the so-called Ph1 of ALL is moreproximal than in CML, and that the bcr gene is notinvolved.99-"t' This suggests that the bcr-abl rear-rangement is more specific to CML than the Phtchromosome itself, and also shows that in ALL theactivation of c-abl, if any, must be promoted by adifferent mechanism.

Burkitt's lymphomna with the t(8;22) variantBurkitt's lymphoma (BL) is a monoclonal malignantproliferation of B cells, almost always related toEpstein-Barr virus in the so-called endemic regionsof black Africa, but not in other regions.'t12 It isperhaps the only human malignancy with an obliga-

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tory chromosome rearrangement: t(8;14) in 75% ofcases, t(2;8) in 5%, and t(8;22) in 20% ofcases. 103-106

In BL translocations, the chromosome break-points invariably occur at the site of the proto-oncogene c-myc on chromosome 8 (8q24) and at thesite of immunoglobulin genes on the partnerchromosome: heavy chains on chromosome14 (14q32), kappa light chain on chromosome2 (2pl2), and lambda light chain on chromosome22 (22q1 1). This fact has raised considerable interest,and it is impossible to review here all the publica-tions on the molecular biology of BL, even in theless frequent t(8;22) variant.107- 1( In brief, BL isthe first example in which chromosome transloca-tion and gene transposition have been shown toinduce oncogenesis by proto-oncogene (c-myc)activation, as proposed by Klein in a propheticpaper."' In BL with t(8;22), the breakpoint occursat 22q11-2,"12 inside the Ig lambda cluster, eitherinside IGLC, 23 or between IGLV and IGLC 23 or inIGL V.29At the DNA level many features distinguish the

t(8;22) variant of BL from the common t(8;14). (1)c-myc stays on chromosome 8, where an incomingCk or VX gene from chromosome 22 is fused in ahead-to-tail fashion (same orientation). (2) Thebreakpoint is mostly far (>45 kb) downstream froman intact c-myc.26 (3) There are very few cases (linesBL37 and KK124) in which the breakpoint could becloned and localised at a reachable distance in the 3'flanking region of c-myc. 30) 113

In BL it is generally accepted that c-mvc, an'immortalising' oncogene, is deregulated, becomesconstitutively expressed, and participates in the stillmysterious process of cell transformation. Thisderegulation is relatively easy to explain in some BLwith t(8;14) in which the c-tnvc gene has lost its 5'regulatory exon. or has been placed under thecontrol of an immunoglobulin enhancer,'119 but inmost cases this does not occur, especiallv in thet(8;22) BL variants. A possible deregulating effectof somatic point mutations occurring in criticalnon-coding regions of c-myc has also been advo-cated in the t(8;14) common variants."1 7 Some ofus recently found discrete alterations of the c-mcycrestriction map in BL cell lines with t(8;22), repre-senting somatic point mutations clustering in andaround the first non-coding exon. l 8 We do not knowhow a remote juxtaposition to a lambda Ig gene canproduce such events in the c-myc gene, nor if theyare directly responsible for its deregulation. Theexact role of c-myc in B cell oncogenesis is still notknown, nor is the nature of a possible other coop-erating 'oncogene'.

It was the study of the BL with t(8;22) which

enabled the localisation of the IGL V genes proximalto IGLC at 22q11.29 30 By molecular hybridisationwith Ck probes it was shown that the breakpoint at22qll of the t(8;22) BL type is more proximal thanthat of the Ph' 119 120)Ewing's sarcoma and neuroepitheliomaIn 1983, a specific t(11;22)(q24;q12) translocationwas reported independently by two groups investi-gating fresh tumour cells'2 and established lines'22from Ewing's sarcoma (ES). This finding wasfurther confirmed in a number of cases (more than40).12- 128 Variant translocations such as t(2;11;22),t(9;20;22),'2' and t(2;12;22) 129 were also reported,indicating that chromosome 22 was the criticalchromosome. The ES breakpoint appears to be themost distal on chromosome 22 of all the rearrange-ments described on this chromosome. This wassuspected already upon standard cytoFeneticexamination of the first cases reported, 21 2 andfurther confirmed to be distal to Ck'3" and to bcr'3'(fig 2). It is proximal to c-sis which is translocatedonto chromosome 11 without being modified oractivated. 131 132An apparently identical translocation was also

found in peripheral neuroepithelioma'33 withoutimplication of c-sis. 134 Very recently, a similartranslocation has been reported in a neuroendocrinetumour of the small intestine.'35 Although there isan identical chromosomal lesion in all thesetumours, we still do not know what DNA sequencefrom chromosome 22, if any, is involved. It shouldbe emphasised that all these malign-rncies have acommon neuronal origin*.

Meningioma and nervouis system malignanciesSporadic meningioma is a relatively benign tumourin which a uniform chromosomal aberration isfound: total or partial loss of one chromosome 22. Itwas first discovered by Zang and Singer' 36 andZankl and Zang'-37 and to date more than 200 caseshave been documented.'38-'40' The constant mono-somy of chromosome 22 is striking, as well as thefact that in about 10t% of the cases only the regiondistal to 22q112 is missing.8 4 42 Interestingly,two recent papers reported the occurrence ofmeningioma in subjects with constitutional abnor-malities of chromosome 22: a ring chromosome 22 inone case143 and a Robertsonian t(14;22) in apedigree with familial meningioma. 144 Loss or rear-rangements of chromosome 22 have also beenreported in central nervous system tumours, such asastrocytomas and gliomas. 14( 143 145 146

Ewing's siirconia. originallyI dcscribcd as a diftftusc endotheliomaiil ot honc.develops in hone tissuc, hut is not ostcogenic.

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The molecular explanation of the tumours associ-ated with total or partial loss of chromosome 22 isstill unknown, but this situation suggests the possi-ble existence on chromosome 22 (distal to 22qll 2 ?)of an 'anti-onco ene', like the Rb] locus onchromosome 13, 7 and the WAGR locus onchromosome 11.148 149 This hypothesis can be testedby investigating RFLPs at chromosome 22 loci, inboth constitutional and tumour DNA of eachsubject, looking for loss of heterozygosity in thelatter. Very recently this approach was used todemonstrate the loss of genes on chromosome 22 inseven subjects with acoustic neuroma. 151)CONSTITUTIONAL ABNORMALITIESBalanced t(l1;22) translocationThis is one of the most frequent balanced chromo-somal translocations in the population and morethan 150 independent families with t(11;22) havebeen reported. 151-153 It is usually discovered infamilies where some subjects are infertile, or inchildren carrying a small supernumerary chromo-some 22 corresponding to der(22). 152 154 These chil-dren are trisomic for the distal part of chromosome11 and the proximal part of chromosome 22. Theyexhibit a characteristic phenotype151 155 and thediagnosis can be made at first sight. The dysmorphicsyndrome is similar to that of trisomy llqter155 andis very different from that caused by the rare trisomy22.156158 Analysis of prometaphase chromosomesshowed that in all the families the breakpoint is thesame, at 11q23-2 and 22q11-2.'53 This suggests thatthere is a preferential recombination site on bothchromosomes, if one admits a pluricentric origin ofthe chromosomal accident.At the molecular level, in situ hybridisation

experiments with a Ck probe suggested that thebreakpoint is in the Ck cluster'30 or proximal to it. 130aHowever, after selection of the der(11) chromosomeof a similar case by flow sorting and hybridisation withboth Ck and Vk probes, some of us found that itcarried both genes.159 This would indicate that, atleast in the latter case, the breakpoint is proximal toIGLV and the most proximal of all breakpoints at22ql1 (fig 2).Unbalanced aberrations of chromosome 22As one would expect with a chromosome rich inearly replicating R bands, there are very fewexamples of true constitutional chromosome 22aneusomy. Complete trisomy 22 is probably lethalbecause it is frequently found in early abortedembryos. It has been detected in stillborn babies,either homogeneously or in mosaic form.16 ' Thepublished cases of complete or partial trisomy 22 inliving subjects are in fact generally related to theabove mentioned recurrent t(11;22).

There are few cases of true partial imbalance ofsmall segments of the chromosome 22 long arm, duemore often to unbalanced translocations than toaccidents affecting only chromosome 22.158 161

Ring chromosome 22 is rare and gives a well definedphenotype with mental retardation, cerebellar atax-ia, and peculiar facial dysmorphism. 162 163

The cat eye syndrome comprises ocular coloboma,imperforate anus, cardiac defects, mental retarda-tion, and a small supernumerary bisatellitedchromosome. 164 165 The nature of this extra chromo-some is difficult to identify on a strict cytogeneticbasis and it has been considered to represent trisomyor tetrasomy of 22pter-*>qll66 167 or partial trisomyof chromosome 13.168 Molecular hybridisation withchromosome 22 specific DNA probes recentlysolved this question, showing that the isodicentricchromosome carries three or four copies of D22S9mapping at 22q 11.169 It hybridised with IGLV butnot with D22S117) which places the breakpointbetween these two loci (fig 2).

The DiGeorge syndrome (DGS) is a dysembryo-genic disorder characterised by developmentalabnormalities of the III to IV pharyngeal pouch,featuring aplasia or hypoplasia of the thymus andthe parathyroid glands, cardiac malformations, andcervicofacial dysmorphism.171 The clinical picture isdominated by early cardiac failure. In survivors,hypocalcaemia or susceptibility to infections due tocellular immunodeficiency are the majormanifestations. 172 Familial cases have been reportedin 14 out of 123 families. 172-182De la Chapelle et al'76 described an unbalanced

translocation, -22, +der(20) ,t(20;22)(ql 1 ;ql 1), infour affected children from the same family. Thesepatients were trisomic for the short arm of chromo-some 20 and monosomic for the pter-*qll region ofchromosome 22. After this observation, other casesin which the same proximal part of one chromosome22 was missing have been reported in subjectsexhibiting unbalanced chromosomal translocationsbetween 22 and various autosomes: 3, 10, or 20,1834,18)) and 1 (O Raoul, personal communication).Another familial case with an apparently balancedt(2;22)(c13;qI1-1) translocation has been re-ported.' ' If we count the older observations ofDGS with chromosome 22 monosomy,'85 186 thereare now 14 cases in which this syndrome is associ-ated with an aberration involving chromosome 22.There are only two cases in which cytogeneticaberrations were present but did not apparentlyinvolve chromosome 22. 172 187 It is therefore temp-ting to consider, as proposed by de la Chapelle et

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al,t76 that the disease is caused by a DNA defect onchromosome 22, in the juxtacentromeric part of thelong arm, at least in some cases. In this regard theDGS would apear to be an inborn error ofmorphogenesis rather than a teratogenic disease.The defect might involve still unknown developmen-tal genes, and obviously this deserves furthermolecular studies with cloned probes mapping in theproximal region of 22q. On this line, Cannizzaro andEmanuel'89 investigated two cases of DGS in whichthe 22pter-*qll region was lost and the 22ql 1-*qterregion was translocated to the long arm of chromo-some 10183 or 4.180 By in situ hybridisation with a Ckprobe they showed that, in both cases, the break-point was proximal to an intact IGLC cluster. Thisplaces the DGS breakpoint in the same region as BLwith t(8;22), or more proximally (fig 2).

ENZYMOPATHIESThere are three monogenic recessive diseases due towell documented structural defects of enzymesencoded on chromosome 22.

Hurler and Scheie syndromes (mucopolysacchar-idosis I; McKusick number 25280), a lysosomaldisease due to a-L-iduronidase deficiency (locusIDUA). 190-192Metachromatic leucodystrophy (sulphatide lipido-sis or cerebroside sulphatase deficiency;McKusick number 25010), a lysosomal diseasedue to arylsulphatase A deficiency (locusARSA). 19319Recessive congenital methaemoglobinaemia(NADH methaemoglobin reductase or NADHdiaphorase deficiency; McKusick number 25080)due to cytochrome b5 reductase deficiency (locusDIAl)196 197 with its two forms: type I withoutmental retardation (enzyme defect restricted toRBC) and type II with mental retardation andneurological symptoms (systemic enzymedeficiency).198 199A fourth enzymopathy, galactosialidosis (com-

bined neuraminidase deficiency and 13 galactosidasedeficiency or Goldberg syndrome; McKusick num-ber 25654), is a lysosomal disease featuring acombination of mucopolysaccharidosis and sphing-olipidosis, due to lack of the 32 K protective proteinwhich stabilises both 13 galactosidase and neuramini-dase against intralysosomal digestion (locusPPGB). 6 2(Each of these diseases poses interesting problems,

mainly regarding their clinical and biological hetero-geneity. They will be solved, hopefully, whencloned probes are available to unravel the featuresof the normal and abnormal genes involved.

73

A MORBID MAP OF CHROMOSOME 22 (FIG 2)We have seen that, despite its short size, chromo-some 22 has a rich pathology. We show in fig 2 thelocation on chromosome 22 of the different siteswhere pathological events give rise to a knowndisease. As pointed out by Yu et a1211' and Canniz-zaro et al,2(L1 22qll is a hot spot of chromosomebreakage. It is also the site of active DNA rearra-ngements, either normal, yielding an active lambdaIg gene, or abnormal, causing Burkitt's lymphoma,CML, or ALL. The proximal region of the long armis also involved in two developmental diseases, cateye syndrome and DiGeorge syndrome.

Burkitt's lymphoma and CML were the firstmodels in which it was shown that a translocationcan produce a harmful gene fusion. How it isharmful is not yet known. Other malignancies, likeEwing's sarcoma, meningioma, neuroepithelioma,neuroendocrine tumour, and now acoustic neuro-ma, are still unchallenged enigmas at the DNAlevel. Interestingly, they are all derived from nervetissue, even possibly Ewing's sarcoma.2t13 There islittle doubt that the new generation of mappingmethods214 will soon provide a complete map of thischromosome and help to solve these problems.

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Correspondence and requests for reprints to Profes-sor Jean-Claude Kaplan, INSERM U 129, Institut dePathologie Mol6culaire, CHU Cochin, 75014 Paris,France.

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Gene mapping and medical genetics - Journal of Medical ... › content › jmedgenet › 24 › 2 › 65.full.pdftein for galactosidase (PPGB)." With the excep-tion of blood group