title: Novel and recurrent mutations in the C-terminal domain of COMP cluster in two distinct regions and result in a spectrum of phenotypes within the pseudoachondroplasia -- multiple epiphyseal dysplasia disease group.
abstract: Pseudoachondroplasia (PSACH) and some forms of multiple epiphyseal dysplasia (MED) result from mutations in the gene encoding cartilage oligomeric matrix protein (COMP). COMP is a large pentameric glycoprotein found predominantly in the extracellular matrix of cartilage, tendon, and ligament. As a modular protein, it is composed of a coiled-coil domain, four type II (T2) repeats, eight type III (T3) repeats, and a large globular C-terminal domain (CTD). The majority (>85%) of COMP mutations causing PSACH or MED are found in the exons encoding the T3 repeats, and the disease mechanism has been characterised in detail. Much less is known about disease-causing mutations in the CTD; in 10 years only seven mutations have been identified. In this study, we describe eight novel and two recurrent mutations that we have recently identified in patients with PSACH or MED. Interestingly, these mutations result in a spectrum of disease, ranging from mild MED to severe PSACH. Mapping of all known COMP CTD mutations on a three-dimensional model of the C-terminal domain shows that the CTD mutations cluster in two distinct regions. These regions are probably important in stabilising the T3-CTD structure and mediating intra- or intermolecular interactions.
authors.affiliation: National Genetics Reference Laboratory (Manchester) and Regional Genetics Service, St Mary's Hospital, Manchester, M13 0JH, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Kennedy
authors.forename: Gail C
authors.initials: GC
authors.lastname: Jackson
authors.forename: Faye S
authors.initials: FS
authors.lastname: Barker
authors.forename: Seema
authors.initials: S
authors.lastname: Nundlall
authors.forename: Jordi
authors.initials: J
authors.lastname: Bella
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wright
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Katherine
authors.initials: K
authors.lastname: Neas
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thompson
authors.forename: Rob
authors.initials: R
authors.lastname: Elles
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
mesh_terms: D000130:Achondroplasia / Q000000981:diagnostic imaging / Q000235:genetics*; D064236:Cartilage Oligomeric Matrix Protein; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000235:genetics*; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D064235:Matrilin Proteins; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011859:Radiography
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human