Human Molecular Genetics Advance Access originally published online on May 7, 2008
Human Molecular Genetics 2008 17(16):2417-2423; 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 Department of Plastic and Reconstructive Surgery, Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 9DU, UK 3 MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK
* To whom correspondence should be addressed. Tel: +44 1865222619; Fax: +44 1865222500; Email: awilkie{at}hammer.imm.ox.ac.uk
Received March 9, 2008; Accepted April 30, 2008
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.