Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University Hospital, Umeå, Sweden.
Am J Hum Genet. 2010 Feb 12;86(2):126-37. doi: 10.1016/j.ajhg.2009.12.018. Epub 2010 Feb 4.
Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.
剥脱性骨软骨炎是一种关节软骨和软骨下骨碎片从关节表面脱落的疾病。我们分析了一个五代家系，该家系中受累成员患有常染色体显性遗传性剥脱性骨软骨炎。全基因组连锁分析将聚集蛋白聚糖 (ACAN) 鉴定为该疾病的主要候选基因。ACAN 的序列分析显示，受累个体存在杂合性错义突变 (c.6907G > A)，导致聚集蛋白聚糖 G3 结构域 C 型凝集素中的 p.V2303M 氨基酸取代，该结构域介导与软骨细胞外基质中其他蛋白质的相互作用。用重组突变和野生型 G3 蛋白进行的结合研究表明，V2303M 蛋白丧失了与纤维连接蛋白-1、纤维连接蛋白-2 和腱糖蛋白-R 的相互作用。从患者软骨中纯化的聚集蛋白聚糖的质谱分析证实，V2303M 聚集蛋白聚糖是产生的，并存在于组织中。我们的研究结果为家族性剥脱性骨软骨炎的病因提供了分子机制，并表明聚集蛋白聚糖 C 型凝集素相互作用对体内软骨功能的重要性。
