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- Title
The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.
- Authors
Mata, Ignacio F.; Yongwoo Jang; Chun-Hyung Kim; 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
- Abstract
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.
- Subjects
PARKINSON'S disease &; genetics; GENETIC mutation; X chromosome abnormalities; GENETIC code; C-terminal binding proteins
- Publication
Molecular Neurodegeneration, 2015, Vol 10, Issue 1, p1
- ISSN
1750-1326
- Publication type
Article
- DOI
10.1186/s13024-015-0045-4