Matrilin-3-type multiple epiphyseal dysplasia (MED) mutations in matnlin-1 and matrilin-4 new disease-causing loci for MED?

Matrilins(matnlin1-4)是多种结缔组织的模块化接头蛋白，与胶原纤维和其他基质成分相互作用。所有四种matrilin都在软骨中表达，但只有人类matrlin-3基因的突变与多发性骨骺发育不良(MED)有关，MED是一种以轻度侏儒症和早发性骨关节炎为特征的骨骼发育不良。大多数MATN3 MED突变是错误的，主要影响蛋白的von Willebrand因子A样域(von Willebrand factorA-like，VWFA)结构域的保守残基。最近的数据表明，突变的matnlin-3以错误折叠蛋白的形式保留在RER中，并在软骨细胞中引发未折叠的蛋白反应和ER应激信号。除了MATN3，编码comp、COL9A1-A3和DDTST的基因突变已在MED患者中被发现然而，约50%的病例的致病突变(S)/基因(S)尚不清楚，考虑到matnlin家族成员的保守结构、表达模式和异源寡核苷酸特性，matn1和matn4是附加MED基因座的很好候选者。在本研究中，我们计划将MATNS-Xype MED突变引入munne matn1/matn4的保守位置并在哺乳动物细胞中表达，以研究突变对matnlin-1和matnlin-4体外运输和分泌的影响，以确定这些突变在体内的后果。我们将通过将特定的MATN3 MED突变引入小鼠matnlin-4的第一个VWFA结构域来建立一个免疫模型。此外，我们已经通过“欧洲骨骼发育不良网络”共同启动了MED患者的MATN1/MATN4突变筛查，这些方法允许我们排除或包括作为MED致病基因的MATN1/MATN4。

Matrilins (matnlin1-4) are modular adaptor proteins of various connective tissues interacting with collagen fibrils and other martix constituents. All four matrilins are expressed in cartilage but only mutations in the human matrilin-3 gene {MATN3) are associated with multiple epiphyseal dysplasia (MED), a skeletal dysplasia charactenzed by mild dwarfism and early-onset osteoarthritis Most of the MATN3 MED mutations are missense, which pnmanly affect conserved residues of the ßsheet of the von Willebrand factor A-like (vWFA) domain of the protein Recent data indicate that mutant matnlin-3 is retained within the rER as misfolded protein and elicits unfolded protein response and ER stress signaling in chondrocytes The disorder is genetically heterogeneous, and in addition to MATN3, mutations in the genes encoding COMP, COL9A1-A3 anö DTDST have been identified in MED patients, however, the causative mutation(s)/gene(s) tn about 50% of the cases are not known Taking into account the conserved structure, expression pattern and hetero-oligomenzation properties of matnlin family members, MATN1 and MATN4 are good candidates for additional MED loci In this proposal, we plan to introduce MATNS-Xype MED mutations into the conserved sites of munne Matn1/Matn4 and express them in mammalian cells to investigate the effects of mutations on the trafficking and secretion of matnlin-1 and matnlin-4 in vitro In order to determine the in vivo consequence of such mutations, we will generate a munne model by introducing a specific MATN3 MED mutation into the first vWFA domain of mouse matnlin-4 In addition, we have initiated mutation screening of MATN1/MATN4 in MED patients via the "European Skeletal Dysplasia Network" Collectively, these approaches allow us to exclude or include MATN1/MATN4 as MED-causing loci.