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

• Type of Material: Article
• Authors: Ignacio F. Mata, Veterans Affairs Puget Sound Health Care System; Yongwoo Jang, Harvard Medical School; Chun-Hyung Kim, Harvard Medical School; David S. Hanna, University of Washington; Michael O. Dorschner, University of Washington; Ali Samii, Veterans Affairs Puget Sound Health Care System; Pinky Agarwal, Evergreen Hospital Medical Center; John W. Roberts, Virginia Mason Medical Center; Olga Klepitskaya, University of Colorado; David R. Shprecher, University of Utah; Kathryn A. Chung, Portland Veterans Affairs Medical Center; Stewart Factor, Emory University; Alberto J. Espay, University of Cincinnati; Fredy J. Revilla, University of South Carolina; Donald S. Higgins, Samuel Stratton Veterans Affairs Medical Center; Irene Litvan, University of California; James B. Leverenz, Cleveland Clinic; Dora Yearout, Emory University; Miguel Inca-Martinez, Instituto Nacional de Ciencias Neurologicas; Erica Martinez, Emory University; Tiffany R. Thompson, Veterans Affairs Puget Sound Health Care System; Brenna A. Cholerton, University of South Carolina; Shu-Ching Hu, Veterans Affairs Puget Sound Health Care System; Karen L. Edwards, University of California; Kwang-Soo Kim, Harvard Medical School; Cyrus P. Zabetian, Veterans Affairs Puget Sound Health Care System
• Language: English
• Date: 2015-12
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Mata et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13024-015-0045-4
• Title of Journal or Parent Work: Molecular Neurodegeneration
• ISSN: 1750-1326
• Volume: 10
• Issue: 1
• Grant/Funding Information: A gift from the Dolsen Foundation.; This work was supported by grants from the National Institutes of Health (P50 NS062684, R01 NS065070, R01 NS084869) and the Department of Veterans Affairs (1I01BX000531)
• Research Categories: Psychology, General; Biology, Neuroscience

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.