Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis
Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis
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DOI：
10.1093/hmg/ddm024
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
John, Simon W. M.
中科院分区：
文献类型：
--
作者：
Gould, Douglas B.;Marchant, Jeffrey K.;John, Simon W. M.
眼前节发育不全（ASD）是一组复杂且知之甚少的疾病。大部分患有ASD的个体发展为青光眼，这是视网膜神经节细胞死亡导致失明的主要原因。视神经发育不全被认为有不同的原因，是儿童失明的主要原因。在这里，我们表明，在IV型胶原蛋白α 1（Col4a1）基因突变可以导致ASD和视神经发育不全。COL4A1是几乎所有基底膜的主要成分。突变导致突变型COL4A1蛋白不分泌，而是在细胞内积累。基底膜异常可能，因此，有助于表型。该突变还诱导内质网应激，因此细胞内应激可能有助于发病机制。Col4a1突变的总体后果取决于遗传背景。在一种遗传背景下，该突变导致严重的ASD伴眼内压异常和视神经发育不全。在不同的遗传背景下，ASD和视神经发育不全都被挽救，我们已经确定了一个单一的显性基因座，赋予表型修饰。
Ocular anterior segment dysgenesis (ASD) is a complex and poorly understood group of conditions. A large proportion of individuals with ASD develop glaucoma, a leading cause of blindness resulting from retinal ganglion cell death. Optic nerve hypoplasia is thought to have distinct causes and is a leading cause of blindness in children. Here, we show that a mutation in the type IV collagen alpha 1 (Col4a1) gene can cause both ASD and optic nerve hypoplasia. COL4A1 is a major component of almost all basement membranes. The mutation results in non-secretion of the mutant COL4A1 proteins, which instead accumulate within cells. Basement membrane abnormalities may, therefore, contribute to the phenotype. The mutation also induces endoplasmic reticulum stress and so intracellular stress may contribute to pathogenesis. The overall consequence of the Col4a1 mutation depends on genetic context. In one genetic context, the mutation causes severe ASD with intraocular pressure abnormalities and optic nerve hypoplasia. In a different genetic context, both the ASD and optic nerve hypoplasia are rescued, and we have identified a single dominant locus that confers the phenotypic modification.