期刊
PLOS GENETICS
卷 12, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006090
关键词
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资金
- National Natural Science Foundation of China [81000397, 81170853, 30901646]
- Science and Technology Planning Project of Guangdong Province, China [2010B031600130, 2011B031300013]
- Natural Science Foundation of Guangdong Province, China [8151503102000019, S2013010015618]
- Outstanding Young Scholar in Talents Project of Guangdong province
- Guandong High-level Personnel of Special Support Program
- Joint Shantou International Eye Center of Shantou University
- Chinese University of Hong Kong [10-019, 10-020, 10-021, 10-022]
- Yangfan Plan of Talents Recruitment Grant
Cataracts are a significant public health problem with no provenmethods 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.
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