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

• Published in: European journal of human genetics : EJHG 2016-01, Vol.24 (1), p.37-43
• Main Authors: Petit, Florence, Jourdain, Anne-Sophie, Holder-Espinasse, Muriel, Keren, Boris, Andrieux, Joris, Duterque-Coquillaud, Martine, Porchet, Nicole, Manouvrier-Hanu, Sylvie, Escande, Fabienne
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions; Adolescent; Adult; Aged; Base Sequence; Body Patterning - genetics; Child; Clonal deletion; Deoxyribonucleic acid; DNA; European Continental Ancestry Group; Female; Fingers & toes; Fingers - abnormalities; Gene deletion; Gene expression; Gene Expression Regulation, Developmental; Genes, Dominant; Haplotypes; Hedgehog protein; Hedgehog Proteins - genetics; Heredity; Humans; Hypertrichosis - ethnology; Hypertrichosis - genetics; Hypertrichosis - pathology; Male; Middle Aged; Molecular Sequence Data; Morphogenesis; Pedigree; Phenotype; Phenotypes; Polydactyly; Polydactyly - ethnology; Polydactyly - genetics; Polydactyly - pathology; Regulatory sequences; Sequence Analysis, DNA; Sequence Deletion; Silencer Elements, Transcriptional; Transcription; Transcription factors
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2015.53

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.