Missense mutations in COL8A2, the gene encoding the α2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy
Missense mutations in COL8A2, the gene encoding the α2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy
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DOI：
10.1093/hmg/10.21.2415
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发表时间：
2001-10-02
影响因子：
3.5
通讯作者：
Black, GCM
中科院分区：
文献类型：
--
作者：
Biswas, S;Munier, FL;Black, GCM
角膜透明性由其内皮维持，内皮在内皮营养不良中功能异常，导致角膜混浊。这组病症包括Fuchs角膜内皮营养不良（FECD）（在发达国家进行的角膜移植的最常见适应症之一）、后部多形性营养不良（PPCD）和先天性遗传性内皮营养不良（CHED）。对一个三代早发性FECD家族的全基因组搜索显示与D1 S2830存在显著连锁（Z（max）= 3.72，θ = 0.0）。对关键区域的细化限定了染色体1p34.3-p32的6-7 cM间隔，其中存在COL 8A 2基因。这编码VIII型胶原蛋白的703个氨基酸的α 2链，VIII型胶原蛋白是一种短链胶原蛋白，其是内皮基底膜的组分并且代表强候选基因。其编码序列的分析确定了一个错义突变（gln 455 lys）内的三螺旋结构域的蛋白质在这个家庭。FECD和PPCD患者的突变分析表明，在家族性和散发性FECD病例以及PPCD单个家族中存在进一步的错义置换。这是第一次描述任何角膜内皮营养不良或与人类疾病相关的VIII型胶原突变的分子基础。这表明FECD和PPCD的潜在发病机制可能与VIII型胶原在影响神经嵴来源的角膜内皮细胞的终末分化中的作用的干扰有关。
Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Z(max) = 3.72, theta = 0.0). Refinement of the critical region defined a 6-7 cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.