Homozygous loss-of-function mutation of the LEPREL1 gene causes severe non-syndromic high myopia with early-onset cataract
Homozygous loss-of-function mutation of the LEPREL1 gene causes severe non-syndromic high myopia with early-onset cataract
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DOI：
10.1111/cge.12309
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发表时间：
2014-12-01
影响因子：
3.5
通讯作者：
Xia, K.
中科院分区：
文献类型：
--
作者：
Guo, H.;Tong, P.;Xia, K.
高度近视是一种严重的视力障碍，可增加视网膜变性、视网膜下出血、脉络膜新生血管、白内障和视网膜脱离的风险。我们招募了一个常染色体隐性高度近视家庭，受影响的受试者同时出现早发性白内障、视网膜变性和其他并发症。通过靶向捕获和全外显子组测序，我们在LEPREL1基因中发现了一个纯合无义突变，该突变导致在第5个氨基酸（c.13C>T; p.Q5X）的翻译过早终止，与表型共分离。LEPREL1编码脯氨酸羟化酶，称为脯氨酸3-羟化酶2 (P3H2)，这是一种依赖于2-氧戊二酸的双加氧酶，可使胶原羟基化。结果表明，LEPREL1在眼睛发育中起重要作用，该基因的纯合性功能缺失突变可导致严重高度近视和早发性白内障。我们的研究也强烈提示胶原蛋白修饰的破坏是高度近视和白内障的发病机制之一。
High myopia is a severe visual impairment which can increase the risk of retinal degeneration, subretinal hemorrhage, choroidal neovascularization, cataract and retinal detachment. We recruited an autosomal-recessive high myopia family, with affected subjects who also present early-onset cataract, retinal degeneration and other complications. Using targeted capturing and whole exome sequencing, we identified a homozygous non-sense mutation in the LEPREL1 gene which causes premature termination of the translation at the fifth amino acid (c.13C>T; p.Q5X), co-segregating with the phenotypes. LEPREL1 encodes a proline hydroxylase called prolyl 3-hydroxylase 2 (P3H2), a 2-oxoglutarate-dependent dioxygenase that hydroxylates collagens. The results show that LEPREL1 plays an important role in eye development and homozygous loss-of-function mutation of this gene can cause severely high myopia and early-onset cataract. Our study also strongly suggests that the disruption of collagen modification is one of the pathogenic mechanisms of high myopia and cataract.