Identification of cartilage oligomeric matrix protein (COMP) gene mutations in patients with pseudoachondroplasia and multiple epiphyseal dysplasia

ABSTRACT Cartilage oligomeric matrix protein (COMP) belongs to the thrombospondin family and is a homopentamer primarily expressed in cartilage. Mutations in the COMP gene result in the autosomal dominant chondrodysplasias pseudoachondroplasia (PSACH) and some types of multiple epiphyseal dysplasia (MED), which are characterized by mild to severe short-limb dwarfism and early-onset osteoarthritis. We have generated COMP-null mice to study the role of COMP in vivo. These mice show no anatomical, histological, or ultrastructural abnormalities and show none of the clinical signs of PSACH or MED. Northern blot analysis and immunohistochemical analysis of cartilage indicate that the lack of COMP is not compensated for by any other member of the thrombospondin family. The results also show that the phenotype in PSACH/MED cartilage disorders is not caused by the reduced amount of COMP.

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Novel mutations in the cartilage oligomeric matrix protein gene identified in two Taiwanese patients with pseudoachondroplasia and multiple epiphyseal dysplasia

Pediatrics & Neonatology ◽

10.1016/j.pedneo.2017.10.006 ◽

2018 ◽

Vol 59 (4) ◽

pp. 412-414 ◽

Cited By ~ 1

Author(s):

Wei-De Lin ◽

I-Ching Chou ◽

Chung-Hsing Wang ◽

Fuu-Jen Tsai

Keyword(s):

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Protein Gene ◽

Multiple Epiphyseal Dysplasia ◽

Novel Mutations ◽

Matrix Protein Gene ◽

Epiphyseal Dysplasia

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Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene

Nature Genetics ◽

10.1038/ng0795-330 ◽

1995 ◽

Vol 10 (3) ◽

pp. 330-336 ◽

Cited By ~ 351

Author(s):

M.D. Briggs ◽

S.M.G. Hoffman ◽

L.M. King ◽

A.S. Olsen ◽

H. Mohrenweiser ◽

...

Keyword(s):

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Protein Gene ◽

Multiple Epiphyseal Dysplasia ◽

Matrix Protein Gene ◽

Epiphyseal Dysplasia

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Disruption of Extracellular Matrix Structure May Cause Pseudoachondroplasia Phenotypes in the Absence of Impaired Cartilage Oligomeric Matrix Protein Secretion

Journal of Biological Chemistry ◽

10.1074/jbc.m601976200 ◽

2006 ◽

Vol 281 (43) ◽

pp. 32587-32595 ◽

Cited By ~ 28

Author(s):

Markus Schmitz ◽

Alexander Becker ◽

Alexander Schmitz ◽

Christian Weirich ◽

Mats Paulsson ◽

...

Keyword(s):

Extracellular Matrix ◽

Endoplasmic Reticulum ◽

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Major Element ◽

Multiple Epiphyseal Dysplasia ◽

Transfected Cells ◽

Primary Chondrocytes ◽

Cell Matrix ◽

Epiphyseal Dysplasia

Pseudoachondroplasia and multiple epiphyseal dysplasia are two dominantly inherited chondrodysplasias associated with mutations in cartilage oligomeric matrix protein (COMP). The rarely available patient biopsies show lamellar inclusions in the endoplasmic reticulum. We studied the pathogenesis of these chondrodysplasias by expressing several disease-causing COMP mutations in bovine primary chondrocytes and found that COMP-associated chondrodysplasias are not exclusively storage diseases. Although COMP carrying the mutations D469Δ and D475N was retained within the endoplasmic reticulum, secretion of COMP H587R was only slightly retarded. All pseudoachondroplasia mutations impair cellular viability and cause a disruption of the extracellular matrix formed in alginate culture irrespective of the degree of cellular retention. The mutation D361Y associated with the clinically milder disease multiple epiphyseal dysplasia gave mild retention and limited matrix alterations, but the transfected cells showed normal viability. The effect of mutated COMP on matrix formation and cell-matrix interaction may be a major element in the pathogenesis of COMP-associated chondrodysplasias.

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