A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb.

Journal article

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: Furniss, D; Lettice, L; Taylor, I; Critchley, P; Giele, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Human molecular genetics
• Volume: 17
• Issue: 16
• Pages: 2417-2423
• Publication date: 2008-08-01
• DOI: 10.1093/hmg/ddn141
• EISSN: 1460-2083
• ISSN: 0964-6906
• Language: English
• Keywords: Male; Animals; Haplotypes; Hedgehog Proteins; Mice, Transgenic; Polydactyly; Humans; Genetic Linkage; Extremities; Hand Deformities, Congenital; Molecular Sequence Data; Gene Expression Regulation, Developmental; Cohort Studies; Sequence Alignment; Female; Enhancer Elements, Genetic; Chromosomes, Human, Pair 7; Pedigree; Mice; Microsatellite Repeats; Base Sequence; Mutation