title: A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb.
abstract: A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T>C variant in the human ZRS, previously thought to represent a neutral polymorphism, acts as a dominant allele with reduced penetrance. We found this variant in three independently ascertained probands from southern England with triphalangeal thumb, demonstrated significant linkage of the phenotype to the variant (LOD = 4.1), and identified a shared microsatellite haplotype around the ZRS, suggesting that the probands share a common ancestor. An individual homozygous for the 295C allele presented with isolated bilateral triphalangeal thumb resembling the heterozygous phenotype, suggesting that the variant is largely dominant to the wild-type allele. As a functional test of the pathogenicity of the 295C allele, we utilized a mutated ZRS construct to demonstrate that it can drive ectopic anterior expression of a reporter gene in the developing mouse forelimb. We conclude that the 295T>C variant is in fact pathogenic and, in southern England, appears to be the most common cause of triphalangeal thumb. Depending on the dispersal of the founding mutation, it may play a wider role in the aetiology of this disorder.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Furniss
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lettice
authors.forename: Indira B
authors.initials: IB
authors.lastname: Taylor
authors.forename: Paul S
authors.initials: PS
authors.lastname: Critchley
authors.forename: Henk
authors.initials: H
authors.lastname: Giele
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hill
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D000818:Animals; D001483:Base Sequence; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D015331:Cohort Studies; D004742:Enhancer Elements, Genetic; D005121:Extremities / Q000196:embryology / Q000254:growth & development*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008040:Genetic Linkage; D006228:Hand Deformities, Congenital / Q000196:embryology / Q000235:genetics*; D006239:Haplotypes; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017689:Polydactyly / Q000196:embryology / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human