COL5A1 Signal Peptide Mutations Interfere with Protein Secretion and Cause Classic Ehlers-Danlos Syndrome
COL5A1 Signal Peptide Mutations Interfere with Protein Secretion and Cause Classic Ehlers-Danlos Syndrome
复制标题
DOI：
10.1002/humu.20887
复制
发表时间：
2009-02-01
期刊：
影响因子：
3.9
通讯作者：
De Paepe, Anne
中科院分区：
文献类型：
--
作者：
Symoens, Sofie;Malfait, Fransiska;De Paepe, Anne
经典Ehler-Danlos综合征(EDS)是一种遗传性结缔组织病，以皮肤过度伸展、萎缩性瘢痕、关节过度活动和全身组织脆性为特征。COL5A1和COL5A2编码V型胶原前α1和前α2链的突变，在类似于50%的典型EDS患者中被发现。大多数突变导致COL5A1等位基因不起作用，这是由于在一个COL5A1转录本中引入了过早的停止密码子。少数突变会影响V型胶原中心螺旋结构域的结构。我们发现，前原α1(V)-胶原链的信号肽(SP)区域的突变导致了典型的EDS。错义突变(p.L25R和p.L25P)位于关键的疏水性SP核心，该核心是蛋白质转运到内质网所必需的。结果，突变的V型前胶原保留在细胞内，导致细胞外基质中V型胶原的数量减少，并干扰了胶原纤维的形成。我们的发现进一步支持了这一观察结果，即V型(PRO)胶原的可获得性降低是经典EDS发病机制中的一个关键因素和共同机制。(C)2008年Wiley-Liss，Inc.
Classic Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disease characterized by skin hyperextensibility, atrophic scarring, joint hypermobility and generalized tissue fragility. Mutations in COL5A1 and COL5A2, encoding the type V collagen pro alpha 1- and pro alpha 2-chain, are found in similar to 50% of patients with classic EDS. The majority of mutations lead to a non-functional COL5A1 allele, as a result of the introduction of a premature stopcodon in one COL5A1 transcript. A minority of mutations affect the structure of the type V collagen central helical domain. We show that mutations in the signal peptide (SP) domain of the prepro alpha 1(V)-collagen chain cause classic EDS. The missense mutations (p.L25R and p.L25P) are located in the crucial hydrophobic SP core, which is indispensible for preprotein translocation into the endoplasmic reticulum. As a result, mutant type V procollagen is retained within the cell, leading to a decreased amount of type V collagen in the extracellular matrix and disturbed collagen fibrillogenesis. Our findings further support the observation that decreased availability of type V (pro) collagen is a key factor and a shared mechanism in the pathogenesis of classic EDS. (C) 2008 Wiley-Liss, Inc.