Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts.
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.
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.
Jian-Huan
JH
Chen
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Chukai
C
Huang
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Bining
0000-0002-4308-3729
B
Zhang
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Shengjie
S
Yin
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Jiajian
J
Liang
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Ciyan
C
Xu
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Yuqiang
Y
Huang
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Ling-Ping
LP
Cen
Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.
Tsz-Kin
0000-0001-7863-7229
TK
Ng
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Ce
C
Zheng
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Shaobin
S
Zhang
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Haoyu
0000-0003-0676-4610
H
Chen
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.
Chi-Pui
CP
Pang
Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
Mingzhi
M
Zhang
D000293:Adolescent; D000328:Adult; D001343:Autophagy / Q000235:genetics; D001483:Base Sequence; D002386:Cataract / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D004252:DNA Mutational Analysis; D004847:Epithelial Cells / Q000473:pathology*; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007908:Lens, Crystalline / Q000166:cytology / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C484342:RRAGA protein, human; D020559:Monomeric GTP-Binding Proteins