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“Hand language” Fiorella Gurrieri Istituto di Genetica Medica, Università Cattolica S. Cuore Roma II European Course in Clinical Dysmorphology Rome, March 28 th -29 th , 2008
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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

Paleonthology and phylogeny

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

Panderichthydis

Ichthyostega

Anterior limb of Achantostega(still only acquatic)

Posterior limb of Ichthyostega

Limb morphology for all tetrapods was clearly defined from early on….

Embryology

The patterning of the embryo is highly conservedthroughout species

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

THE LIMB BUD

Signaling pathways in the developing limb bud

Duijf et. Al, Hum Mol Genet 2003

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

Brunner and van Bokhoven, Cell cycle 2007

P63 –o-pathyes

P63 mutations and related conditions

Brunner and van Bokhoven, Cell cycle 2007

The EEC SYNDROME

(Image from the web site)

Rinne et al., AJMG 2006

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 P63 -o-pathy : SHFM4

Paternal grandmother

father

propositus

From G. Neri

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)

Incidence is 1:90.000 almost all over the world….

Pathogenesis of Split hand/foot: failure in the central AER

Duijf et. Al, Hum Mol Genet 2003

Another connection between digits and ectoderm:the ODDD (OculoDentoDigitalDysplasia) due to GJA1 (conn 43) mutations

Kelly et al., EJDermat 2006

Hand-Foot –Genital syndrome

Utsch et al., AJMG A, 2007

In the majority of patients the mutation is a polyA expansion

wt polyA+

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)

ROBINOW and type B brachydactyly(distal phalanges)

ROR2ROR2 (LOF) mutations(LOF) mutations in Robinow in Robinow and type Band type BBrachBrachyydadaccttyylly (GOF)y (GOF)

(Van Bokhoven et al., Nat Genet, 2000)

ROR2 knockROR2 knock--out out mousemouse

UlnUlnarar--mammarmammary syndrome andy syndrome and TBX3TBX3 mutationsmutations

TBX3 TBX3 mutations inmutations in UMSUMS

(Bamshad et al., 1999)

FROM OVERLAPPING PHENOTYPES TO INTERACTING GENES

•Holt-Oram

•Townes Brocks

•Okihiro

•Feingold? Radialdefect

GI atresia

Heartdefect

TBX5 mutations in Holt-Oram

ASDVSDPDA

SALL1 mutations in Townes-Brocks

(Marlin et al., 1999)

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

ANOTHER RECURRENT PHENOTYPE IS THAT OF THE ORAL

F. GurrieriL. Garavelli

ADDITIONAL ORAL ANOMALIES

F. Gurrieri

L. Garavelli

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

MOLECULAR BIOLOGY

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

HOXA13

HOXA13

HOXD13

HOXD13

TBX3TBX3--55

GLI3GLI3

P63P63

EVCEVC

ROR2ROR2

SALL

1SA

LL1 --

44

GJA1GJA1??

IHHIHH

DLX

5D

LX5--

66


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