Journal
NEUROBIOLOGY OF AGING
Volume 61, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2017.08.030
Keywords
Familial amyotrophic lateral sclerosis; HNRNPA1; TBK1; VCP; Whole-exome sequencing analysis; Stress granule
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Funding
- KAKENHI from Ministry of Education, Culture, Sports, Science and Technology of Japan [22129001, 22129002]
- Ministry of Health, Welfare and Labour, Japan [H23-Jitsuyoka (Nanbyo)-Ippan-004, H26-Jitsuyoka (Nanbyo)-Ippan-080]
- Grants-in-Aid for Scientific Research [17J03762, 15H05871, 15K21731] Funding Source: KAKEN
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To elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) in the Japanese population, we conducted whole-exome sequencing analysis of 30 FALS families in whom causative mutations have not been identified in previous studies. Consequently, whole-exome sequencing analysis revealed novel mutations in HNRNPA1, TBK1, and VCP. Taken together with our previous results of mutational analyses by direct nucleotide sequencing analysis, a microarray-based resequencing method, or repeat-primed PCR analysis, causative mutations were identified in 41 of the 68 families (60.3%) with SOD1 being the most frequent cause of FALS (39.7%). Of the mutations identified in this study, a novel c.862/1018C>G (p.P288A/340A) mutation in HNRNPA1 located in the nuclear localization signal domain of hnRNPA1, enhances the recruitment of mutant hnRNPA1 into stress granules, indicating that an altered nuclear localization signal activity plays an essential role in amyotrophic lateral sclerosis pathogenesis. (C) 2017 Elsevier Inc. All rights reserved.
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