title: Trinucleotide expansion mutations in the cartilage oligomeric matrix protein (COMP) gene.
abstract: Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are two human autosomal dominant skeletal dysplasias characterized by variable short stature, joint laxity and early-onset degenerative joint disease. Both disorders can result from mut-ations in the gene for cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein. About one-third of PSACH cases result from heterozygosity for deletion of one codon within a very short triplet repeat, (GAC)5, which encodes five consecutive aspartic acid residues within the calmodulin-like region of the COMP protein. We have identified two expansion mut-ations in this repeat: an MED patient carrying a (GAC)6allele and a PSACH patient carrying a (GAC)7allele. These are among the shortest disease-causing triplet repeat expansion mutations described thus far, and are the first identified in a GAC repeat. A unique feature of this sequence is that expansion as well as shortening of the repeat can cause the same disease. In cartilage, both patients have rough endoplasmic reticulum inclusions in chondrocytes. The inclusions are also present in tendon tissue and can be reproduced in cultured tendon cells, suggesting that the pathophysiology of disease is similar in both cartilage and tendon.
authors.affiliation: Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Cedars-Sinai Research Institute, and Department of Pediatrics, UCLA School of Medicine, Los Angeles, CA 90048, USA.
authors.forename: E
authors.initials: E
authors.lastname: Délot
authors.forename: L M
authors.initials: LM
authors.lastname: King
authors.forename: M D
authors.initials: MD
authors.lastname: Briggs
authors.forename: W R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: D H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D000130:Achondroplasia / Q000235:genetics / Q000473:pathology; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology; D064236:Cartilage Oligomeric Matrix Protein; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D064235:Matrilin Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D013710:Tendons / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D017931:DNA Primers; D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human