Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia
Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia
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DOI：
10.1038/ng573
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发表时间：
2001-08-01
期刊：
影响因子：
30.8
通讯作者：
Briggs, MD
中科院分区：
文献类型：
--
作者：
Chapman, KL;Mortier, GR;Briggs, MD
多发性骨骺发育不良（MED）是一种相对轻度和临床可变的骨软骨发育不良，主要特征为骨骺骨化延迟和不规则以及早发性骨关节炎（1-3）。编码软骨寡聚基质蛋白（COMP）和IX型胶原蛋白（COL 9A 2和COL 9A 3）的基因突变先前已显示可导致不同形式的MED（参考文献10）。4-13）。这些主要形式的MED（EDM 1 -3）是由编码软骨细胞外基质（ECM）结构蛋白的基因突变引起的;这些蛋白质在体外以高亲和力相互作用（14，15）。MED的隐性形式（EDM 4）也有报道;它是由畸形性发育不良硫酸盐转运蛋白基因（16）（SLC 26 A）突变引起的。对不与EDM 1 -3基因连锁的常染色体显性MED家族进行全基因组筛选（17），为2号染色体短臂（2 p24-p23）上的MED基因座提供了重要的遗传证据，并在关键区域内搜索了编码matrilin-3的候选基因MATN 3（参考文献18）。Matrilin-3是存在于软骨ECM中的寡聚蛋白。我们已经确定了两个不同的错义突变的外显子编码血管性血友病因子A（vWFA）结构域matrilin-3在两个无关的家庭MED（EDM 5）。这些是在编码matrilin蛋白家族的任何基因中鉴定的第一个突变，并证实了matrilin-3在软骨和骨的发育和体内平衡中的作用。
Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia, primarily characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis(1-3). Mutations in the genes encoding cartilage oligomeric matrix protein (COMP) and type IX collagen (COL9A2 and COL9A3) have previously been shown to cause different forms of MED (refs. 4-13). These dominant forms of MED (EDM1-3) are caused by mutations in the genes encoding structural proteins of the cartilage extracellular matrix (ECM); these proteins interact with high affinity in vitro(14,15). A recessive form of MED (EDM4) has also been reported; it is caused by a mutation in the diastrophic dysplasia sulfate transporter gene(16) (SLC26A). A genomewide screen of family with autosomal-dominant MED not linked to the EDM1-3 genes(17) provides significant genetic evidence for a MED locus on the short arm of chromosome 2 (2p24-p23), and a search for candidate genes identified MATN3 (ref. 18), encoding matrilin-3, within the critical region. Matrilin-3 is an oligomeric protein that is present in the cartilage ECM. We have identified two different missense mutations in the exon encoding the von Willebrand factor A (vWFA) domain of matrilin-3 in two unrelated families with MED (EDM5). These are the first mutations to be identified in any of the genes encoding the matrilin family of proteins and confirm a role for matrilin-3 in the development and homeostasis of cartilage and bone.