title: Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis.
abstract: Spondylocostal dysostosis (SCD) is an inherited disorder with abnormal vertebral segmentation that results in 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). Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4). These genes are all essential components of the Notch signalling pathway, which has multiple roles in development and disease. Previously, only a single SCD-causative missense mutation was described in HES7. In this study, we have identified two new missense mutations in the HES7 gene in a single family, with only individuals carrying both mutant alleles being affected by SCD. In vitro functional analysis revealed that one of the mutant HES7 proteins was unable to repress gene expression by DNA binding or protein heterodimerization.
authors.affiliation: ] Developmental Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia.
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Merridee A
authors.initials: MA
authors.lastname: Wouters
authors.forename: Peter D
authors.initials: PD
authors.lastname: Turnpenny
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D004413:Dysostoses / Q000150:complications / Q000235:genetics*; D005190:Family; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D013131:Spine / Q000002:abnormalities*; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C486601:HES7 protein, human