基因突变导致病理性近视。

gene mutations cause pathological myopia.

机构信息

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, Guangdong, China.

出版信息

J Med Genet. 2023 Sep;60(9):918-924. doi: 10.1136/jmg-2022-108978. Epub 2023 Mar 22.

DOI:10.1136/jmg-2022-108978

PMID:36948574

Abstract

PURPOSE

Genetic factors play a prominent role in the pathogenesis of pathological myopia (PM). However, the exact genetic mechanism of PM remains unclear. This study aimed to determine the candidate mutation of PM in a Chinese family and explore the potential mechanism.

METHODS

We performed exome sequencing and Sanger sequencing in a Chinese family and 179 sporadic PM cases. The gene expression in human tissue was investigated by RT-quantitative real-time PCR (RT-qPCR) and immunofluorescence. Cell apoptotic rates were tested by annexin V-APC/7AAD and flow cytometry. knock-in mice with point mutation were generated for measuring myopia-related parameters.

RESULTS

We screened a novel variant (c.689T>C; p.F230S) in a Chinese family with PM, and another rare mutation (c.1015C>A; p.L339M) was identified in 179 unrelated cases with PM. RT-qPCR and immunofluorescence confirmed the expression of PSMD3 in human eye tissue. Mutation of decreased the mRNA and protein expression, causing apoptosis of human retinal pigment epithelial cells. In in vivo experiments, the axial length (AL) of mutant mice increased significantly compared with that of wild-type mice (p<0.001).

CONCLUSIONS

A new potential pathogenic gene, , in a PM family was identified, and it may be involved in the elongation of AL and the development of PM.

摘要

目的

遗传因素在病理性近视（PM）的发病机制中起重要作用。然而，PM的确切遗传机制尚不清楚。本研究旨在确定一个中国家族中 PM 的候选突变，并探讨其潜在机制。

方法

我们对一个中国家族和 179 例散发性 PM 病例进行了外显子组测序和 Sanger 测序。通过 RT-定量实时 PCR（RT-qPCR）和免疫荧光法检测人组织中的基因表达。通过 Annexin V-APC/7AAD 和流式细胞术检测细胞凋亡率。生成具有点突变的 knock-in 小鼠，以测量与近视相关的参数。

结果

我们在一个 PM 家系中筛选出一种新型突变（c.689T>C；p.F230S），在 179 例无关的 PM 病例中鉴定出另一种罕见突变（c.1015C>A；p.L339M）。RT-qPCR 和免疫荧光法证实了 PSMD3 在人眼组织中的表达。突变降低了 mRNA 和蛋白表达，导致人视网膜色素上皮细胞凋亡。在体内实验中，与野生型小鼠相比，突变型小鼠的眼轴长度（AL）显著增加（p<0.001）。