Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts.
Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts.
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mTORC1 通路中 RagA GTPase 突变与常染色体显性白内障相关
DOI：
10.1371/journal.pgen.1006090
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发表时间：
2016-06
期刊：
影响因子：
4.5
通讯作者：
Zhang M
中科院分区：
文献类型：
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作者：
Chen JH;Huang C;Zhang B;Yin S;Liang J;Xu C;Huang Y;Cen LP;Ng TK;Zheng C;Zhang S;Chen H;Pang CP;Zhang M
白内障是一个重大的公共卫生问题，没有经过证实的预防方法。发现新的疾病机制，描绘新的治疗靶点，在白内障的预防和治疗的重要性。在此，我们报告了RagA GT3（RRAGA）的突变，这是机械雷帕霉素复合物1（mTORC 1）的关键调节因子，与常染色体显性白内障相关。我们在一个常染色体显性青少年发作性白内障家族中进行了全外显子组测序，并在对dbSNP数据库和来自公共和内部外显子组数据库的至少123，000个对照染色体进行过滤后，确定了RRAGA中与疾病共分离的新型p.Leu60Arg突变。在对另外22个先天性或青少年发病的白内障家系和142名无关患者进行的RRAGA随访直接筛查中，发现两名无关患者（p.Leu60Arg和c.-Leu 60 Arg）的RRAGA突变。16G>A）。在人透镜上皮细胞中的功能研究揭示，RRAGA突变对mTORC 1信号传导产生有害影响，包括增加RRAGA向溶酶体的重新定位、上调mTORC 1磷酸化、下调自噬、改变细胞生长或损害启动子活性。这些数据表明，与常染色体显性白内障相关的RRAGA突变通过破坏mTORC 1信号传导在疾病中发挥作用。
Cataracts are a significant public health problem with no proven methods for prevention. Discovery of novel disease mechanisms to delineate new therapeutic targets is of importance in cataract prevention and therapy. Herein, we report that mutations in the RagA GTPase (RRAGA), a key regulator of the mechanistic rapamycin complex 1 (mTORC1), are associated with autosomal dominant cataracts. We performed whole exome sequencing in a family with autosomal dominant juvenile-onset cataracts, and identified a novel p.Leu60Arg mutation in RRAGA that co-segregated with the disease, after filtering against the dbSNP database, and at least 123,000 control chromosomes from public and in-house exome databases. In a follow-up direct screening of RRAGA in another 22 families and 142 unrelated patients with congenital or juvenile-onset cataracts, RRAGA was found to be mutated in two unrelated patients (p.Leu60Arg and c.-16G>A respectively). Functional studies in human lens epithelial cells revealed that the RRAGA mutations exerted deleterious effects on mTORC1 signaling, including increased relocation of RRAGA to the lysosomes, up-regulated mTORC1 phosphorylation, down-regulated autophagy, altered cell growth or compromised promoter activity. These data indicate that the RRAGA mutations, associated with autosomal dominant cataracts, play a role in the disease by acting through disruption of mTORC1 signaling.