Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts

Jian-Huan Chen; Chukai Huang; Bining Zhang; Shengjie Yin; Jiajian Liang; Ciyan Xu; Yuqiang Huang; Ling-Ping Cen; Tsz-Kin Ng; Ce Zheng; Shaobin Zhang; Haoyu Chen; Chi-Pui Pang; Mingzhi Zhang

doi:10.1371/journal.pgen.1006090

Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts

PLoS Genet. 2016 Jun 13;12(6):e1006090. doi: 10.1371/journal.pgen.1006090. eCollection 2016 Jun.

Authors

Jian-Huan Chen^{1

2}, Chukai Huang¹, Bining Zhang¹, Shengjie Yin¹, Jiajian Liang¹, Ciyan Xu¹, Yuqiang Huang¹, Ling-Ping Cen¹, Tsz-Kin Ng², Ce Zheng¹, Shaobin Zhang¹, Haoyu Chen¹, Chi-Pui Pang^{1

2}, Mingzhi Zhang¹

Affiliations

¹ Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
² Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Autophagy / genetics
Base Sequence
Cataract / genetics*
Cell Proliferation / genetics
DNA Mutational Analysis
Epithelial Cells / pathology*
Exome / genetics
Female
Humans
Lens, Crystalline / cytology
Lens, Crystalline / pathology*
Male
Mechanistic Target of Rapamycin Complex 1
Middle Aged
Monomeric GTP-Binding Proteins / genetics*
Multiprotein Complexes / genetics*
Multiprotein Complexes / metabolism
Sequence Analysis, DNA
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism
Young Adult

Substances

Multiprotein Complexes
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
RRAGA protein, human
Monomeric GTP-Binding Proteins

Supplementary concepts

Cataract, Autosomal Dominant

Grants and funding

This study was supported in part by research grants from National Natural Science Foundation of China (No. 81000397 and 81170853 to JHC and 30901646 to HC), Science and Technology Planning Project of Guangdong Province, China (No. 2010B031600130 to JHC and 2011B031300013 to HC), Natural Science Foundation of Guangdong Province, China (No. 8151503102000019 to MZ and S2013010015618 to JHC), Outstanding Young Scholar in Talents Project of Guangdong province (to JHC), Guandong High-level Personnel of Special Support Program and Yangfan Plan of Talents Recruitment Grant (to JHC), and Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong (No. 10-019, 10-020, 10-021 and 10-022 to MZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.