دورية أكاديمية
Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts.
العنوان: | Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts. |
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المؤلفون: | 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 |
المصدر: | PLoS Genetics, Vol 12, Iss 6, p e1006090 (2016) |
بيانات النشر: | Public Library of Science (PLoS), 2016. |
سنة النشر: | 2016 |
المجموعة: | LCC:Genetics |
مصطلحات موضوعية: | Genetics, QH426-470 |
الوصف: | 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. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 1553-7390 1553-7404 |
Relation: | http://europepmc.org/articles/PMC4905677?pdf=render; https://doaj.org/toc/1553-7390; https://doaj.org/toc/1553-7404 |
DOI: | 10.1371/journal.pgen.1006090 |
URL الوصول: | https://doaj.org/article/790739b9d31646a1bfd2fedd534c22fe |
رقم الأكسشن: | edsdoj.790739b9d31646a1bfd2fedd534c22fe |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 15537390 15537404 |
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DOI: | 10.1371/journal.pgen.1006090 |