期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 97, 期 3, 页码 1212-1217出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.3.1212
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资金
- NIAMS NIH HHS [R37 AR037318, R01 AR036794] Funding Source: Medline
- NICHD NIH HHS [P30-HD18655, P30 HD018655] Funding Source: Medline
Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition shown in some cases to be caused by mutations in genes encoding cartilage oligomeric matrix protein or type IX collagen. We studied a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak log(10) odds ratio for linkage score of 3.87 for markers D20S93 and D20S164. Reverse transcription-PCR performed on the muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3 domain of alpha 3(IX) collagen. Direct sequencing of genomic DNA confirmed the presence of a splice acceptor mutation in intron 2 of the COL9A3 gene (intervening sequence 2, C-A, -1) only in affected family members. By electron microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough endoplasmic reticulum containing linear lamellae of alternating electron-dense and electron-lucent material, reflecting abnormal processing of mutant protein. Type IX collagen chains appeared normal in size and quantity but showed defective cross-linking by Western blotting. The novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A3 gene. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen.
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