Symoens Sofie, Malfait Fransiska, Renard Marjolijn, André Josette, Hausser Ingrid, Loeys Bart, Coucke Paul, De Paepe Anne
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Hum Mutat. 2009 Feb;30(2):E395-403. doi: 10.1002/humu.20887.
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 proalpha1- and proalpha2-chain, are found in approximately 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 preproá1(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.
经典型埃勒斯-当洛综合征（EDS）是一种遗传性结缔组织疾病，其特征为皮肤过度伸展、萎缩性瘢痕形成、关节活动过度以及全身组织脆弱。编码V型胶原蛋白原α1链和原α2链的COL5A1和COL5A2基因发生突变，在约50%的经典型EDS患者中可检测到。大多数突变导致一个COL5A1等位基因无功能，这是由于在一个COL5A1转录本中引入了提前终止密码子。少数突变影响V型胶原蛋白中央螺旋结构域的结构。我们发现前原α1（V）-胶原蛋白链信号肽（SP）结构域的突变会导致经典型EDS。错义突变（p.L25R和p.L25P）位于关键的疏水性SP核心区域，该区域对于前体蛋白转运至内质网至关重要。因此，突变型V型前胶原保留在细胞内，导致细胞外基质中V型胶原蛋白数量减少，胶原纤维形成受到干扰。我们的研究结果进一步支持了以下观点：V型（前）胶原蛋白可用性降低是经典型EDS发病机制中的关键因素和共同机制。
