GBF1 deficiency causes cataracts in human and mouse.

IF 3.8 2区生物学 Q2 GENETICS & HEREDITY

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-07 DOI:10.1007/s00439-024-02697-8

Weimin Jia, Chenming Zhang, Yalin Luo, Jing Gao, Chao Yuan, Dazhi Zhang, Xiaopei Zhou, Yongyao Tan, Shuang Wang, Zhuo Chen, Guigang Li, Xianqin Zhang

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引用次数: 0

Abstract

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.

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GBF1 缺乏会导致人类和小鼠白内障。

晶状体的任何混浊都可被定义为白内障，而晶状体上皮细胞通过维持晶状体的平衡，在保证晶状体透明度方面发挥着至关重要的作用。虽然已有多个先天性白内障致病基因的报道，但晶状体混浊的机制仍不清楚。本研究收集了一个患有先天性白内障的大家庭，通过基因分析发现了 GBF1 基因中的一个病理突变（c.3857 C > T, p.T1287I）；该家族中所有受影响的个体都携带这一杂合突变，而未受影响的家族成员则不携带。在人类晶状体上皮细胞系中进行的功能研究显示，这种突变导致 GBF1 蛋白水平降低。敲除内源性 GBF1 会激活未折叠蛋白反应信号通路中的 XBP1s，并以不依赖于 mTOR 的方式增强自噬。杂合子Gbf1基因敲除小鼠也表现出典型的白内障表型。总之，我们的研究确定了 GBF1 是先天性白内障的新型致病基因。此外，我们还发现 GBF1 缺乏会激活未折叠蛋白反应并导致自噬增强，这可能会导致晶状体不透明。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Genetics 生物-遗传学

CiteScore

10.80

自引率

3.80%

发文量

审稿时长

1 months

期刊介绍： Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.