The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis

European Journal of Human Genetics : EJHG
F PetitFabienne Escande

Abstract

The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of-function of the Zone of Polarizing Activity Regulatory Sequence, the only limb-specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located ~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype.

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Citations

Mar 16, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Jacob W P PotuijtAnnelies de Klein
Feb 28, 2018·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Magdalena Harakalova, Folkert W Asselbergs
Oct 16, 2018·The Journal of Hand Surgery, European Volume·Jacob W P PotuijtSteven E R Hovius
Jun 16, 2017·Nature Reviews. Rheumatology·Caroline Ospelt, Mojca Frank-Bertoncelj
Feb 19, 2020·Journal of Feline Medicine and Surgery·Alexia HamelinMarie Abitbol
Sep 28, 2017·Clinical Genetics·T Harel, J R Lupski
Jun 27, 2019·Orphanet Journal of Rare Diseases·Jennifer E Posey
Oct 9, 2015·Critical Reviews in Biochemistry and Molecular Biology·Lijing YaoPeggy J Farnham
Aug 10, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Caixia XuPeiqiang Su
Sep 9, 2021·Animal Genetics·C MacPhillamyW Y Low

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