title: Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia.
abstract: Mutations in the gene encoding cartilage oligomeric matrix protein ( COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). More than 40 mutations have been identified; however, genotype-phenotype relationships are not well delineated. Further, mutations other than in-frame insertion/deletions and substitutions have not been found, and currently known mutations are clustered within relatively small regions. Here we report the identification of nine novel and three recurrent COMP mutations in PSACH and MED patients. These include two novel types of mutations; the first, a gross deletion spanning an exon-intron junction, causes an exon deletion. The second, a frameshift mutation that results in a truncation of the C-terminal domain, is the first known truncating mutation in the COMP gene. The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs ( P=0.0003) and elsewhere in the COMP gene ( P=0.0007). Patients carrying mutations within the five-aspartates repeat (aa 469-473) in the seventh CLR were extremely short (below -6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations ( P=0.0024). These findings expand the mutation spectrum of the COMP gene and highlight genotype-phenotype relationships, facilitating improved genetic diagnosis and analysis of COMP function in humans.
authors.affiliation: Laboratory for Bone and Joint Deseases, SNP Research Center, RIKEN, c/o Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Mabuchi
authors.forename: Noriyo
authors.initials: N
authors.lastname: Manabe
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Haga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitoh
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawaji
authors.forename: Kazuya
authors.initials: K
authors.lastname: Tamai
authors.forename: Junichiro
authors.initials: J
authors.lastname: Hamada
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nakamura
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
authors.forename: Mamori
authors.initials: M
authors.lastname: Kimizuka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Takatori
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000130:Achondroplasia / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D001483:Base Sequence; D064236:Cartilage Oligomeric Matrix Protein; D002461:Cell Line, Transformed; D004392:Dwarfism / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D064235:Matrilin Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D011859:Radiography; D017384:Sequence Deletion; D012720:Severity of Illness Index
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human