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“Hand language”
Fiorella GurrieriIstituto di Genetica Medica, Università Cattolica S. Cuore Roma
II European Course in Clinical DysmorphologyRome, March 28th-29th, 2008
What is this all going to be about?
It is about the knowledge that people interested in the field of limb malformations have gathered so far from observations and progresses in many different fields such as:
•Paleonthology and phylogeny
•Embryology
•Epidemiology
•Clinical genetics
•Molecular biology
FRASNIAN FAM TOURNAIS VISEAN NAMURAN
OSTEOLEPIFORMS
OBRUCHEVICHTHYIDS ACANTHOSTEGA
ICHTHYOSTEGA
TULERPETON
CRASSIGYRINUS
LOXOMMATOIDEA
TEMNOSPONYLI
MICROSAURIA
COLOSTEIDAE
ANTHRACOSAURIA
AMNIOTE
PANDERICHTHYS
378 367 362 350 332 318
The paradigm of limb development in tetrapods has been conserved throughout evolution for the past 400 millions years……
It all started with Panderichthys, an about 100cm long fish, which is considered the transitional form from finned fishes to tetrapods
Anterior limb of Achantostega(still only acquatic)
Posterior limb of Ichthyostega
Limb morphology for all tetrapods was clearly defined from early on….
FGF10 (meso)
FGF8 (ecto) + FGF4
Let`s now ask a more basic question: Where and How to make a limb in the body embryo?
6 weeks human embryo
Wnt2b + TBX5
Wnt8c + TBX4
anterior boundary of Hox6c expression
EPIDEMIOLOGY
Prevalence of limb defects of any type
0.6 - 0.7 : 1000 births (including livebirths, stillbirths and elective terminations)
(McGuirk CK et al., Pediatrics 2001)
ETIOLOGYChromosome abnormalities 6%
Monogenic conditions 24%
Teratogens 4%
Vascular disruption 35%
Unknown 32%
Clinical geneticsi.e. Limb phenotypes
We will not talk about classification also because there willbe changes in the nomenclature in the near future
A variety of genes is related to a huge number of different phenotypes, but lets distinguish:
•Limbs-only phenotypes or non-syndromal limb defects
•Syndromal limb defects
Different manifestations of the ADULT syndrome
Excessive freckling
Hypodontia
Hypoplastic nipple
Rinne et al, Eur J Hum Genet 2006
(Acro-Dermato-Ungual-Lacrimal-Tooth)
Yang et al., Nature 1999
Mills et al., Nature 1999
P63 Knock-out mice show:
• impaired craniofacial development
• abnormal limb morphogenesis
• Defective ectodermalgrowth
NON SYNDROMAL SPLIT HAND-SPLIT FOOT
•SHFM1 7q22 (DLX5 and 6 candidates)
•SHFM2 Xq26 (defined by linkage analysis)
•SHFM3 10q25 (Duplication of Dactylin)
•SHMF4 3q (P63)
•SHFM5 2q3 (several candidate genes)
Another connection between digits and ectoderm:the ODDD (OculoDentoDigitalDysplasia) due to GJA1 (conn 43) mutations
Kelly et al., EJDermat 2006
OtherOther HOXA13 HOXA13 mutations in Handmutations in Hand--FootFoot--Genital syndromeGenital syndrome
(Goodman et al., 2000)
HOXD13 mutations and Synpolydactyly
Heterozygous Homozygous
Polyalanine expansion with gain of function
IHH-Indian hedgehog mutations in brachydactyly type A1 (rudimentary middle
phalanges)
(Gao et al., 2001)
ROR2ROR2 (LOF) mutations(LOF) mutations in Robinow in Robinow and type Band type BBrachBrachyydadaccttyylly (GOF)y (GOF)
(Van Bokhoven et al., Nat Genet, 2000)
FROM OVERLAPPING PHENOTYPES TO INTERACTING GENES
•Holt-Oram
•Townes Brocks
•Okihiro
•Feingold? Radialdefect
GI atresia
Heartdefect
A gene from the same SAL family (SALL4) causes the Okihiro syndrome:
•Radial side defects•Duane anomaly•Associated anomalies (atrialseptal defect, anal stenosis, hearing loss, renal defects, external ear anomalies)
Kohlhase et al., Hum Mol Genet 2002
MYCN mutations in Feingold Syndrome
•Esophageal or duodenal atresia
•MicrocephalyMR
•Hypoplastic thumb, clinod 5th
(Teszas et al, 2006)
FROM OVERLAPPING PHENOTYPES TO INTERACTING GENES
•Holt-Oram TBX5
•Townes Brocks SALL1
•Okihiro SALL4
•Feingold? MYCN
Harvey and Logan, Development, 2006
The overlapping at the phenotypic level reflects interaction during development
Developing limb bud of a zebrafish pectoral fin outgrowth
6 weeks human embryo
Wnt2b + TBX5
Wnt8c + TBX4
What is TBX5 needed for?
wt
HO
Hasson et. al, Development, 2007
A
P
A downstream protein of SALL 4 is TBX5 which in fact causes a clinically similar condition, the Holt Oram syndrome
FACIAL ANOMALIES
F. Gurrieri
Castelluccio-Rinaldi
G. Cocchi
•Asimmetry•Hypertelorism•Anteverted nostrils•Peculiar eyebrows
Cavaliere-Rinaldi
L. Garavelli
DIGITAL ANOMALIES•Clynodactyly•Brachydactyly•Syndactyly•Polydactyly pre- and post-axial
L. Garavelli
G. Cocchi
F. Gurrieri
A number of different gene A number of different gene products are involved in limb products are involved in limb
defects:defects:What do they have in What do they have in
common?common?
Transmembrane receptor with tirosinTransmembrane receptor with tirosin--Kinase Kinase activity: transmitts to the nucleus activity: transmitts to the nucleus informations on tissues polarity informations on tissues polarity
HOXA13HOXA13HOXD13HOXD13
Transmembrane receptor with nuclear Transmembrane receptor with nuclear localization signals (LZ)localization signals (LZ)
CConnexinonnexin 43 43 ((intercellularintercellular comunicationcomunication protein)protein)
ZincZinc--finger finger DNADNA--bindingbinding transcription factortranscription factor
TT--Box Box DNADNA--bindingbinding transcription factortranscription factor
DNADNA--binding binding transactivation of gene expressiontransactivation of gene expressionDNADNA--bindingbinding transcription repression/activationtranscription repression/activation
DNADNA--binding binding trancription regulationtrancription regulation
TBX3TBX3--55
GLI3GLI3
P63P63
EVCEVC
ROR2ROR2
SALL1SALL1--44
ODDDODDD
IHHIHH Local and long distance signalling moleculeLocal and long distance signalling molecule
OFD1OFD1 MoleculeMolecule of the of the ciliaryciliary apparatusapparatus