Identification of twelve mutations in cartilage oligomeric matrix protein (COMP) in patients with pseudoachondroplasia

ArticleinAmerican Journal of Medical Genetics 80(5):510-3 · January 1999with4 Reads
DOI: 10.1002/(SICI)1096-8628(19981228)80:53.0.CO;2-F · Source: PubMed
Abstract
Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthrosis. PSACH is caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). We are reporting on mutations in COMP in 12 patients with PSACH, including ten novel mutations. Eleven of the mutations are in exons 17A, 17B, and 18A, which encode the calcium-binding domains, and one mutation is in exon 19, which encodes part of the carboxy-terminal globular domain. Two of the mutations identified are the common delGAC(1430-1444) in exon 17B, which accounts for 36% of identified PSACH mutations. This report increases the range of mutations in COMP that cause PSACH and provides additional evidence for the importance of the calcium-binding domains and the globular domain to the function of COMP.
    • "PSACH results from a dominantnegative effect of COMP mutations that lead to intracellular retention of pentameric COMP composed of both mutant and wild-type subunits (Briggs et al., 1995; Hecht et al., 1995). Over 100 mutations in COMP have been identified, but one mutation in which aspartic acid residue 469 is deleted, D469del, accounts for approximately 30% of PSACH cases (Briggs et al., 1998; Deere et al., 1998 Deere et al., , 1999). Following the recognition that mutations in COMP cause PSACH, it was shown that mutant COMP retained in the rER participates in premature intracellular assembly of extracellular matrix (Hecht et al., 1995Hecht et al., , 1998b Merritt et al., 2007; Posey et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
    Full-text · Article · May 2014
    • "PSACH results from a dominant-negative effect of COMP mutations that lead to intracellular retention of pentameric COMP composed of both mutant and wild-type subunits (Briggs et al., 1995; Hecht et al., 1995). Over 100 mutations in COMP have been identified, but one mutation in which aspartic acid residue 469 is deleted, D469del, accounts for approximately 30% of PSACH cases (Briggs et al., 1998; Deere et al., 1998 Deere et al., , 1999). Following the recognition that mutations in COMP cause PSACH, it was shown that mutant COMP retained in the rER participates in premature intracellular assembly of extracellular matrix (Hecht et al., 1995Hecht et al., , 1998b Merritt et al., 2007; Posey et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
    Full-text · Article · Jan 2014 · Gene
    • "And the skull X-ray was normal (figure not shown). Briggs et al. (1998), Deere et al. (1998), Hecht et al. (1995, 1998b), Ikegawa et al. (1998), Jackson et al. (2012), Jung et al. (2010), Kennedy et al. (2005a), Loughlin et al. (1998), Mabuchi et al. (2003), Nakashima et al. (2005 "
    [Show abstract] [Hide abstract] ABSTRACT: A 2.75-year-old Chinese boy presented with typical clinical features of pseudoachondroplasia, including disproportionate short-limb short stature, brachydactyly, genu varus and waddling gait. Radiologically, tubular bones were short with widened metaphyses, irregular and small epiphyses; anterior tonguing or beaking of vertebral bodies were characteristic. DNA sequencing analysis of the COMP gene revealed a heterozygous mutation (c.1511G>A, p.Cys504Tyr) in the patient but his parents were unaffected without this genetic change. The missense mutation (c.1511G>A) was not found in 100 healthy controls and has not been reported previously. Our findings expand the spectrum of known mutations in COMP leading to pseudoachondroplasia.
    Full-text · Article · Apr 2013
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