Human Molecular Genetics Advance Access published online on May 7, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn141
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A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb
1 Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK 2 MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK 3 Department of Plastic and Reconstructive Surgery, Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 9DU, UK
* To whom correspondence should be addressed. Tel: +44 1865222619; Fax +44 1865222500; E-mail: awilkie{at}hammer.imm.ox.ac.uk
Received March 9, 2008; Revised April 30, 2008; Accepted April 30, 2008
A locus for triphalangeal thumb, variably associated with preaxial polydactyly, was previously identified in the Zone of Polarizing Activity Regulatory Sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog gene (SHH) 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 3 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 utilised 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 etiology of this disorder.