A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb–polysyndactyly syndrome. (November 2018)

• Record Type: Journal Article
• Authors: Potuijt, Jacob; Baas, Martijn; Sukenik-Halevy, Rivka; Douben, Hannie; Nguyen, Picard; Venter, Deon; Gallagher, Renée; Swagemakers, Sigrid; Hovius, Steven; van Nieuwenhoven, Christianne; Galjaard, Robert-Jan; van der Spek, Peter; Ahituv, Nadav; de Klein, Annelies
• Is Part Of: Genetics in medicine. Volume 20:Number 11(2018)
• Page Start: 1405
• Page End: 1413
• Publication Date: 2018-11
• Subjects: congenital limb deformities -- genetic enhancer elements -- hedgehog protein -- polydactyly -- syndactyly; Medical genetics -- Periodicals; Genetic disorders -- Periodicals; 616.04205
• DOI: 10.1038/gim.2018.18
• Languages: English
• ISSNs: 1098-3600

Abstract

Abstract Purpose The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of triphalangeal thumb–polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. Methods We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescencein situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Results Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Conclusion Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.