title: Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia.
abstract: Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans. Their biological roles are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome). We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted. Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes. Thus, GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype.
authors.affiliation: Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Ana Belinda
authors.initials: AB
authors.lastname: Campos-Xavier
authors.forename: Danielle
authors.initials: D
authors.lastname: Martinet
authors.forename: John
authors.initials: J
authors.lastname: Bateman
authors.forename: Dan
authors.initials: D
authors.lastname: Belluoccio
authors.forename: Lynn
authors.initials: L
authors.lastname: Rowley
authors.forename: Tiong Yang
authors.initials: TY
authors.lastname: Tan
authors.forename: Alica
authors.initials: A
authors.lastname: Baxová
authors.forename: Karl-Henrik
authors.initials: KH
authors.lastname: Gustavson
authors.forename: Zvi U
authors.initials: ZU
authors.lastname: Borochowitz
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Lauréane
authors.initials: L
authors.lastname: Mittaz
authors.forename: Diana
authors.initials: D
authors.lastname: Ballhausen
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D002675:Child, Preschool; D019902:Chondrocytes / Q000378:metabolism*; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004392:Dwarfism / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D005808:Genes, Recessive / Q000235:genetics*; D053673:Glypicans / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010012:Osteogenesis / Q000502:physiology*
chemical_list: C120300:GPC6 protein, human; D053673:Glypicans