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

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

doi:10.1371/journal.pgen.1006090

Jian-Huan Chen, Jian-Huan Chen + Show 24 more

Open Access

https://doi.org/10.1371/journal.pgen.1006090

Copy DOI

Journal: PLoS Genetics	Publication Date: Jun 13, 2016
Citations: 23	License type: CC BY 4.0

Affiliation: Shantou University, Chinese University of Hong Kong

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.

Highlights

Cataracts refer to the clouding of the crystalline lens, and is a significant public health problem [1]
We report that mutations in the RagA GTPase (RRAGA), a key regulator of the mechanistic rapamycin complex 1, are associated with autosomal dominant cataracts
Whole exome sequencing has led to the identification of the RagA GTPase (RRAGA) gene for cataracts and we proceeded to study properties of the RRAGA protein

Summary

Introduction

Cataracts refer to the clouding of the crystalline lens, and is a significant public health problem [1]. Fewer than twenty causative genes for human autosomal dominant cataracts have been identified, almost half of which are crystallin genes [4]. More than half of the familial dominant cataract cases have unknown genetic causes [5], the molecular mechanism of cataracts has not been fully elucidated, and there is no proven method of prevention for cataracts. Deciphering the genetics of hereditary cataracts will improve our knowledge of the disease, and help identify new strategies for prevention and therapy of cataracts. A recent breakthrough in gene mapping, revealing a mutated lanosterol synthase to be a causative gene for autosomal recessive congenital cataracts, has led to the use of lanosterol to reverse protein aggregation in adult onset cataracts in dogs [6]

Methods

Results

Discussion

Conclusion