title: COL1A1 C-propeptide cleavage site mutation causes high bone mass, bone fragility and jaw lesions: a new cause of gnathodiaphyseal dysplasia?
abstract: Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant condition characterized by bone fragility, irregular bone mineral density (BMD) and fibro-osseous lesions in the skull and jaw. Mutations in Anoctamin-5 (ANO5) have been identified in some cases. We aimed to identify the causative mutation in a family with features of GDD but no mutation in ANO5, using whole exome capture and massive parallel sequencing (WES). WES of two affected individuals (a mother and son) and the mother's unaffected parents identified a mutation in the C-propeptide cleavage site of COL1A1. Similar mutations have been reported in individuals with osteogenesis imperfecta (OI) and paradoxically increased BMD. C-propeptide cleavage site mutations in COL1A1 may not only cause 'high bone mass OI', but also the clinical features of GDD, specifically irregular sclerotic BMD and fibro-osseous lesions in the skull and jaw. GDD patients negative for ANO5 mutations should be assessed for mutations in type I collagen C-propeptide cleavage sites.
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: McInerney-Leo
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.|Department of Endocrinology, Royal Brisbane and Women's Hospital, Herston, QLD, 4029, Australia.
authors.forename: E L
authors.initials: EL
authors.lastname: Duncan
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Leo
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Gardiner
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: Bradbury
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Harris
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.|Department of Medical Genetics, Academic Laboratory of Medical Genetics, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Clark
authors.affiliation: Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Discipline of Genetic Medicine, The University of Sydney, Sydney, Australia.|Academic Department of Medical Genetics, Sydney Children's Hospital Network (Westmead), Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Zankl
mesh_terms: D015519:Bone Density / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D007568:Jaw / Q000000981:diagnostic imaging; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011859:Radiography
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
keywords: ANO5; COL1A1; gnathodiaphyseal dysplasia; osteogenesis imperfecta