Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jinan Second People's Hospital, Jinan, China.
Hum Genet. 2024 Nov;143(11):1281-1291. doi: 10.1007/s00439-024-02697-8. Epub 2024 Aug 7.
Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity.
晶状体的任何混浊都可以定义为白内障，晶状体上皮细胞通过维持其体内平衡对保证晶状体透明性起着至关重要的作用。虽然已经报道了几种先天性白内障的致病基因，但晶状体混浊的机制仍不清楚。在这项研究中，收集了一个患有先天性白内障的大家族，遗传分析显示 GBF1 基因存在病理性突变（c.3857C>T，p.T1287I）；该家族所有受影响的个体均携带这种杂合突变，而未受影响的家族成员则没有。在人晶状体上皮细胞系中的功能研究表明，这种突变导致 GBF1 蛋白水平降低。内源性 GBF1 的敲低激活了未折叠蛋白反应信号通路中的 XBP1s，并以 mTOR 非依赖性方式增强自噬。杂合 Gbf1 基因敲除小鼠也表现出典型的白内障表型。总之，我们的研究确定 GBF1 是一种新的先天性白内障致病基因。此外，我们发现 GBF1 缺乏会激活未折叠蛋白反应，并导致自噬增强，这可能导致晶状体混浊。
