The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease

To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). 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...

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Published in:	Molecular neurodegeneration Vol. 10; no. 1; p. 50
Main Authors:	Mata, Ignacio F, Jang, Yongwoo, Kim, Chun-Hyung, Hanna, David S, Dorschner, Michael O, Samii, Ali, Agarwal, Pinky, Roberts, John W, Klepitskaya, Olga, Shprecher, David R, Chung, Kathryn A, Factor, Stewart A, Espay, Alberto J, Revilla, Fredy J, Higgins, Donald S, Litvan, Irene, Leverenz, James B, Yearout, Dora, Inca-Martinez, Miguel, Martinez, Erica, Thompson, Tiffany R, Cholerton, Brenna A, Hu, Shu-Ching, Edwards, Karen L, Kim, Kwang-Soo, Zabetian, Cyrus P
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 24-09-2015 BioMed Central
Subjects:	Adult Age of Onset Analysis Animals Chromosomes Exome - genetics Female Genetic aspects Genetic Predisposition to Disease Genetic research Genotype Humans Male Medical research Medicine, Experimental Middle Aged Mutation - genetics Parkinson Disease - genetics Phenotype Proteins rab GTP-Binding Proteins - genetics Rats Canada
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Summary:	To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1750-1326 1750-1326
DOI:	10.1186/s13024-015-0045-4