Shiga Yukihiro, Hashimoto Kazuki, Fujita Kosuke, Maekawa Shigeto, Sato Kota, Kubo Shintaroh, Kawase Kazuhide, Tokumo Kana, Kiuchi Yoshiaki, Mori Sotaro, Nakamura Makoto, Iwata Takeshi, Nishiguchi Koji M, Nakazawa Toru
Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Neuroscience Division, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Genet Med Open. 2023 Oct 31;2:100839. doi: 10.1016/j.gimo.2023.100839. eCollection 2024.
Pathogenic variants in , , and are associated with primary open-angle glaucoma (POAG) with severe visual field defects. This study aims to understand further POAG-related pathogenic variant(s) based on a cohort of East Asian populations that have not been well-characterized.
We conducted a comprehensive screening of , , and variants in 174 POAG Japanese patients, followed by 8380 population-specific genome sequencing data references, segregation analysis, and functional protein assays to determine pathogenic variants.
Despite the small sample size, 4 variants were novel, 2 of which p.(Cys5Trp) and p.(Thr293Met) were in the gene, and 2 p.(Asn51Thr), and p.(Gln142His) were in the . Notably, the p.(Asn51Thr) missense variant adjacent to the p.(Glu50Lys) variant, a well-known POAG pathogenic variant, was segregated from all proband's family members with POAG. Moreover, in silico and in vitro analyses revealed that the p.(Asn51Thr) protein increased binding instability, interactions of the OPTN-TBK1 complex, and enhanced protein insolubility, likewise the p.(Glu50Lys) protein.
Our findings may provide further genetic insights into rare variants of POAG and support the clear conclusion that p.(Asn51Thr) is a novel likely pathogenic variant.
、和基因中的致病变异与伴有严重视野缺损的原发性开角型青光眼（POAG）相关。本研究旨在基于尚未得到充分表征的东亚人群队列，进一步了解与POAG相关的致病变异。
我们对174例日本POAG患者的、和基因变异进行了全面筛查，随后参考了8380份特定人群的基因组测序数据，进行了家系分析和功能性蛋白质检测，以确定致病变异。
尽管样本量较小，但发现了4个新变异，其中2个（p.(Cys5Trp)和p.(Thr293Met)）位于基因中，2个（p.(Asn51Thr)和p.(Gln142His)）位于基因中。值得注意的是，与著名的POAG致病变异p.(Glu50Lys)相邻的p.(Asn51Thr)错义变异，在所有患有POAG的先证者家庭成员中均被分离出来。此外，计算机模拟和体外分析表明，p.(Asn51Thr)蛋白增加了结合不稳定性、OPTN-TBK1复合物的相互作用，并增强了蛋白不溶性，p.(Glu50Lys)蛋白也是如此。
我们的研究结果可能为POAG的罕见变异提供进一步的遗传学见解，并支持p.(Asn51Thr)是一种新的可能致病变异这一明确结论。
