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A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb.

Authors: Wieczorek, Dagmar  Pawlik, Barbara  Li, Yun  Akarsu, Nurten A  Caliebe, Almuth  May, Klaus J W  Schweiger, Bernd  Vargas, Fernando R  Balci, Sevim  Gillessen-Kaesbach, Gabriele  Wollnik, Bernd 
Citation: Wieczorek D, etal., Hum Mutat. 2010 Jan;31(1):81-9. doi: 10.1002/humu.21142.
Pubmed: (View Article at PubMed) PMID:19847792
DOI: Full-text: DOI:10.1002/humu.21142

Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the "Cuban mutation" of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome, but do not affect lower limb development. We suggest the term "ZRS-associated syndromes" and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS.

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RGD Object Information
RGD ID: 12801438
Created: 2017-03-30
Species: All species
Last Modified: 2017-03-30
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.