title: Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development.
abstract: The generation and homeostasis of bone tissue throughout development and maturity is controlled by the carefully balanced processes of bone formation and resorption. Disruption of this balance can give rise to a broad range of skeletal pathologies. Lethal osteosclerotic bone dysplasia (or, Raine syndrome) is an autosomal recessive disorder characterized by generalized osteosclerosis with periosteal bone formation and a distinctive facial phenotype. Affected individuals survive only days or weeks. We have identified and defined a chromosome 7 uniparental isodisomy and a 7p telomeric microdeletion in an affected subject. The extent of the deleted region at the 7p telomere was established by genotyping microsatellite markers across the telomeric region. The region is delimited by marker D7S2563 and contains five transcriptional units. Sequence analysis of FAM20C, located within the deleted region, in six additional affected subjects revealed four homozygous mutations and two compound heterozygotes. The identified mutations include four nonsynonymous base changes, all affecting evolutionarily conserved residues, and four splice-site changes that are predicted to have a detrimental effect on splicing. FAM20C is a member of the FAM20 family of secreted proteins, and its mouse orthologue (DMP4) has demonstrated calcium-binding properties; we also show by in situ hybridization its expression profile in mineralizing tissues during development. This study defines the causative role of FAM20C in this lethal osteosclerotic disorder and its crucial role in normal bone development.
authors.affiliation: Department of Medical Genetics, Clinical Developmental Sciences, St George's University of London, London, SW17 0RE, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Simpson
authors.forename: R
authors.initials: R
authors.lastname: Hsu
authors.forename: L S
authors.initials: LS
authors.lastname: Keir
authors.forename: J
authors.initials: J
authors.lastname: Hao
authors.forename: G
authors.initials: G
authors.lastname: Sivapalan
authors.forename: L M
authors.initials: LM
authors.lastname: Ernst
authors.forename: E H
authors.initials: EH
authors.lastname: Zackai
authors.forename: L I
authors.initials: LI
authors.lastname: Al-Gazali
authors.forename: G
authors.initials: G
authors.lastname: Hulskamp
authors.forename: H M
authors.initials: HM
authors.lastname: Kingston
authors.forename: T E
authors.initials: TE
authors.lastname: Prescott
authors.forename: A
authors.initials: A
authors.lastname: Ion
authors.forename: M A
authors.initials: MA
authors.lastname: Patton
authors.forename: V
authors.initials: V
authors.lastname: Murday
authors.forename: A
authors.initials: A
authors.lastname: George
authors.forename: A H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001846:Bone Development / Q000235:genetics*; D001848:Bone Diseases, Developmental / Q000235:genetics*; D002135:Calcium-Binding Proteins; D047389:Casein Kinase I; D002871:Chromosome Banding; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010026:Osteosclerosis / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C509696:FAM20C protein, mouse; D011506:Proteins; D047389:Casein Kinase I; C524449:FAM20C protein, human