title: Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia.
abstract: Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia, primarily characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. Mutations in the genes encoding cartilage oligomeric matrix protein (COMP) and type IX collagen (COL9A2 and COL9A3) have previously been shown to cause different forms of MED (refs. 4-13). These dominant forms of MED (EDM1-3) are caused by mutations in the genes encoding structural proteins of the cartilage extracellular matrix (ECM); these proteins interact with high affinity in vitro. A recessive form of MED (EDM4) has also been reported; it is caused by a mutation in the diastrophic dysplasia sulfate transporter gene (SLC26A). A genomewide screen of family with autosomal-dominant MED not linked to the EDM1-3 genes provides significant genetic evidence for a MED locus on the short arm of chromosome 2 (2p24-p23), and a search for candidate genes identified MATN3 (ref. 18), encoding matrilin-3, within the critical region. Matrilin-3 is an oligomeric protein that is present in the cartilage ECM. We have identified two different missense mutations in the exon encoding the von Willebrand factor A (vWFA) domain of matrilin-3 in two unrelated families with MED (EDM5). These are the first mutations to be identified in any of the genes encoding the matrilin family of proteins and confirm a role for matrilin-3 in the development and homeostasis of cartilage and bone.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester, UK.
authors.forename: K L
authors.initials: KL
authors.lastname: Chapman
authors.forename: G R
authors.initials: GR
authors.lastname: Mortier
authors.forename: K
authors.initials: K
authors.lastname: Chapman
authors.forename: J
authors.initials: J
authors.lastname: Loughlin
authors.forename: M E
authors.initials: ME
authors.lastname: Grant
authors.forename: M D
authors.initials: MD
authors.lastname: Briggs
mesh_terms: D000328:Adult; D002648:Child; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005270:Femur Head / Q000000981:diagnostic imaging / Q000473:pathology; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000473:pathology; D008126:Lod Score; D008297:Male; D064235:Matrilin Proteins; D008875:Middle Aged; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D020161:Physical Chromosome Mapping; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary / Q000235:genetics; D011859:Radiography; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D064235:Matrilin Proteins; D014841:von Willebrand Factor