Human Molecular Genetics Advance Access originally published online on September 5, 2008
Human Molecular Genetics 2008 17(23):3761-3766; doi:10.1093/hmg/ddn272
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Mutation of HAIRY-AND-ENHANCER-OF-SPLIT-7 in humans causes spondylocostal dysostosis
1 Developmental Biology Division 2 Sr Bernice Research Program in Inherited Heart Diseases, Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia 3 St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia 4 Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain 5 School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney 2052, Australia 6 Cardiology Department, St Vincent’s Hospital, Sydney 2010, Australia
* To whom correspondence should be addressed. Tel: +61 292958513; Fax: +61 292958501; Email: s.dunwoodie{at}victorchang.edu.au
Received June 11, 2008; Revised July 23, 2008; Accepted August 28, 2008
Spondylocostal dysostosis (SCD) is an inherited disorder that is characterized by the presence of extensive hemivertebrae, truncal shortening and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites (the precursor tissue of the vertebrae, ribs and associated tendons and muscles). Previously, three genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300 [OMIM] ), MESP2 (SCDO2: MIM 608681 [OMIM] ) and LFNG (SCDO3: MIM609813). These genes are all important components of the Notch signaling pathway, which has multiple roles in development and disease. Here we have used autozygosity mapping to identify a mutation in a fourth Notch pathway gene, HAIRY-AND-ENHANCER-OF-SPLIT-7 (HES7), in an autosomal recessive SCD family. HES7 encodes a bHLH-Orange domain transcriptional repressor protein that is both a direct target of the Notch signaling pathway, and part of a negative feedback mechanism required to attenuate Notch signaling. A missense mutation was identified in the DNA-binding domain of the HES7 protein. Functional analysis revealed that the mutant HES7 was not able to repress gene expression by DNA binding or protein heterodimerization. This is the first report of mutation in the human HES7 gene, and provides further evidence for the importance of the Notch signaling pathway in the correct patterning of the axial skeleton.