Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia.
Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia.
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DOI：
10.1002/humu.9286
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发表时间：
2004-11-01
期刊：
影响因子：
3.9
通讯作者：
Ikegawa, Shiro
中科院分区：
文献类型：
--
作者：
Mabuchi, Akihiko;Haga, Nobuhiko;Ikegawa, Shiro
多发性骨骺发育不良（MED）是一种常见的骨骼发育不良，其特征是关节疼痛和僵硬，骨骺骨化延迟和不规则，以及早发性骨关节炎。目前已鉴定出6个与MED相关的基因，包括COMP、COL 9A 1、COL 9A 2、COL 9A 3、DSTDT和MATN 3。MATN 3编码matrilin-3，一种软骨特异性细胞外基质蛋白。迄今为止，已经鉴定了7种不同的MATN 3突变;所有突变均位于A型血管性血友病因子（vWFA）结构域的β折叠区域内，该结构域由外显子2编码。我们检测了27例日本MED患者的MATN 3突变，这些患者可能是常染色体显性遗传，并且已经排除了COMP突变。其中10人有阳性家族史。我们通过PCR和基因组DNA直接测序检测了MATN 3的所有8个外显子。我们在8个不相关的家族中发现了4个错义突变; 2个是新的，2个以前已经被鉴定过。与先前表征的MATN 3突变一样，本研究中鉴定的那些突变聚集在外显子2内，特别是在vWFA结构域的第2 β折叠区（aa. 120-127）。与先前MED中MATN 3突变局限于β折叠区的假设相反，一个新突变（p.F105S）位于β折叠区之外，α螺旋区内。
Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by joint pain and stiffness, delayed and irregular ossification of epiphyses, and early-onset osteoarthritis. Six genes responsible for MED have been identified, including COMP, COL9A1, COL9A2, COL9A3, DSTDT and MATN3. MATN3 encodes matrilin-3, a cartilage-specific extracellular matrix protein. To date, seven different MATN3 mutations have been identified; all are located within the beta-sheet regions of the von Willebrand factor type A (vWFA) domain, which is encoded by exon 2. We examined MATN3 mutations in27 Japanese MED patients who were possibly autosomal dominant inheritance and had been excluded for COMP mutations. Ten of them had a positive family history. We examined all eight exons of MATN3 by PCR and direct sequencing from genomic DNA. We have identified four missense mutations in eight unrelated families; two are novel, and two have been characterized previously. Like previously characterized MATN3 mutations, those identified in this study are clustered within exon 2, specifically in and around the 2nd beta-sheet region of the vWFA domain (aa. 120-127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the beta-sheet regions, one novel mutation (p.F105S) is located outside the beta-sheet region, within an alpha-helix region.