Chen Jian-Huan, Huang Chukai, Zhang Bining, Yin Shengjie, Liang Jiajian, Xu Ciyan, Huang Yuqiang, Cen Ling-Ping, Ng Tsz-Kin, Zheng Ce, Zhang Shaobin, Chen Haoyu, Pang Chi-Pui, Zhang Mingzhi
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.
PLoS Genet. 2016 Jun 13;12(6):e1006090. doi: 10.1371/journal.pgen.1006090. eCollection 2016 Jun.
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.
白内障是一个重大的公共卫生问题，目前尚无经证实的预防方法。发现新的疾病机制以确定新的治疗靶点对于白内障的预防和治疗至关重要。在此，我们报告机械性雷帕霉素复合物1（mTORC1）的关键调节因子RagA GTP酶（RRAGA）中的突变与常染色体显性白内障相关。我们对一个患有常染色体显性青少年型白内障的家族进行了全外显子组测序，在与dbSNP数据库以及来自公共和内部外显子组数据库的至少123,000条对照染色体进行比对后，在RRAGA中鉴定出一个新的p.Leu60Arg突变，该突变与疾病共分离。在对另外22个家族以及142名先天性或青少年型白内障无关患者进行RRAGA的后续直接筛查中，发现两名无关患者（分别为p.Leu60Arg和c.-16G>A）的RRAGA发生了突变。在人晶状体上皮细胞中的功能研究表明，RRAGA突变对mTORC1信号传导产生有害影响，包括RRAGA向溶酶体的重新定位增加、mTORC1磷酸化上调、自噬下调、细胞生长改变或启动子活性受损。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mTORC1信号传导在该疾病中起作用。
