Premium
A novel mutation in the SHH long‐range regulator (ZRS) is associated with preaxial polydactyly, triphalangeal thumb, and severe radial ray deficiency
Author(s) -
AlQattan Mohammad M.,
Al Abdulkareem Ibrahim,
Al Haidan Yazied,
Al Balwi Mohammed
Publication year - 2012
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.35584
Subject(s) - polydactyly , zone of polarizing activity , sonic hedgehog , thumb , limb development , biology , enhancer , genetics , mutation , point mutation , anatomy , ectoderm , gene , transcription factor , embryogenesis
Sonic Hedgehog (SHH) within the posteriorly located zone of polarizing activity is the main controller of the antero‐posterior axis of limb development. The ZRS (zone of polarizing activity regulatory sequence) is a long‐range limb‐specific SHH enhancer. Several point mutations in the ZRS have been described in humans. These mutations cause enhanced SHH activity and ectopic anterior expression of SHH and a variable phenotype of preaxial polydactyly and triphalangeal thumb. Absent thumb or radius has not been reported with ZRS mutations. Here, we report on a family with a variable phenotype of preaxial polydactyly as well as absent thumb and radius, with kidney and cardiac defects. The family was screened for SALL1 , SALL4 , and TBX5 mutations, but all were normal. Finally, they were screened for ZRS mutations, which showed a novel point mutation within the ZRS, NG_009240.1: g.106954C>T (traditional nomenclature: ZRS619C>T) in the five affected members. This mutation was not previously reported in any public domain database, and was not found in our healthy and ethnically matched control individuals or unaffected family members. We hypothesize that interactions of SHH and SALL1 explain the overlapping features of the family described here and patients with Townes–Brocks syndrome. © 2012 Wiley Periodicals, Inc.