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Hum Mutat. 2014 Aug;35(8):945-8. doi: 10.1002/humu.22581. Epub 2014 Jun 3.

A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form.

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California; Institute for Human Genetics, University of California San Francisco, San Francisco, California.

Abstract

Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation.

KEYWORDS:

SHH; Werner mesomelic syndrome; ZRS; enhancer; preaxial polydactyly

PMID:
24777739
PMCID:
PMC4110103
DOI:
10.1002/humu.22581
[Indexed for MEDLINE]
Free PMC Article

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