Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia.

A cosmid clone was isolated that contained an allele for the type II procollagen gene previously shown to be coinherited with primary generalized osteoarthritis in a large family. Affected members of the family had evidence of a mild chondrodysplasia, but they developed progressive osteoarthritic changes in many joints that had no epiphyseal deformities. The clone contained 52 of the 54 exons of the gene. Nucleotide sequencing of greater than 20,000 base pairs from the clone demonstrated that all the coding sequences and all the intron-exon boundaries were normal except for a single base mutation that converted the codon for arginine at position 519 of the alpha 1(II) chain to a codon for cysteine, an amino acid not found in type II collagen from humans or a variety of other species. The mutation was found in all affected members of the family but not in unaffected members or in 57 unrelated individuals. IMAGES:

本研究成功分离得到一株黏粒克隆（cosmid clone），其携带有II型前胶原基因（type II procollagen gene）的一个等位基因；该等位基因此前已被证实与一个大型家系中的原发性全身性骨关节炎（primary generalized osteoarthritis）共遗传。该家系的患病成员表现出轻度软骨发育不良（chondrodysplasia）特征，但在多个无骨骺畸形（epiphyseal deformities）的关节中出现了进行性骨关节炎病变。该黏粒克隆覆盖了该基因54个外显子（exon）中的52个。对该克隆中超过20000个碱基对（base pair）的核苷酸测序结果显示，除一处单碱基突变外，所有编码序列及内含子-外显子边界均正常：该突变将α1(II)链第519位精氨酸（arginine）的密码子（codon）替换为半胱氨酸（cysteine）的密码子；而人类及其他多个物种的II型胶原蛋白（collagen）中均未发现该种氨基酸。该突变存在于该家系的所有患病成员中，但未在未患病成员或57名无关个体中检出。图像：