当前位置: X-MOL 学术Mol. Neurodegener. › 论文详情
The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.
Molecular Neurodegeneration ( IF 8.274 ) Pub Date : 2015-09-25 , DOI: 10.1186/s13024-015-0045-4
Ignacio F Mata,Yongwoo Jang,Chun-Hyung Kim,David S Hanna,Michael O Dorschner,Ali Samii,Pinky Agarwal,John W Roberts,Olga Klepitskaya,David R Shprecher,Kathryn A Chung,Stewart A Factor,Alberto J Espay,Fredy J Revilla,Donald S Higgins,Irene Litvan,James B Leverenz,Dora Yearout,Miguel Inca-Martinez,Erica Martinez,Tiffany R Thompson,Brenna A Cholerton,Shu-Ching Hu,Karen L Edwards,Kwang-Soo Kim,Cyrus P Zabetian

OBJECTIVE To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). METHODS We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. RESULTS We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. CONCLUSIONS Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders.
更新日期:2019-11-01

 

全部期刊列表>>
聚焦商业经济政治法律
跟Nature、Science文章学绘图
智控未来
控制与机器人
化学研究精选
欢迎探索2019年最具下载量的地球科学论文
招募海内外科研人才,上自然官网
基因组学对精准公共卫生的影响,专辑征稿
隐藏1h前已浏览文章
课题组网站
新版X-MOL期刊搜索和高级搜索功能介绍
ACS材料视界
x-mol收录
湖南大学化学化工学院刘松
上海有机所
李旸
大连化物所
香港大学
X-MOL
支志明
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug