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

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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.
Authors:	Furniss, Dominic Lettice, Laura A Taylor, Indira B Critchley, Paul S Giele, Henk Hill, Robert E Wilkie, Andrew O M
Citation:	Furniss D, etal., Hum Mol Genet. 2008 Aug 15;17(16):2417-23. doi: 10.1093/hmg/ddn141. Epub 2008 May 7.
RGD ID:	12801448
Pubmed:	PMID:18463159 (View Abstract at PubMed)
PMCID:	PMC2486440 (View Article at PubMed Central)
DOI:	DOI:10.1093/hmg/ddn141 (Journal Full-text)
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.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
SHH	Human	preaxial polydactyly II		IAGP			RGD
Shh	Rat	preaxial polydactyly II		ISO	RGD:736829		RGD
Shh	Mouse	preaxial polydactyly II		ISO	RGD:736829		RGD

Objects Annotated

Genes (Rattus norvegicus)

Shh (sonic hedgehog signaling molecule)

Genes (Mus musculus)

Shh (sonic hedgehog)

Genes (Homo sapiens)

SHH (sonic hedgehog signaling molecule)

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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.