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

ABSTRACT: 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.

SUBMITTER: Mata IF

PROVIDER: S-EPMC4581468 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Mata Ignacio F IF Jang Yongwoo Y Kim Chun-Hyung CH Hanna David S DS Dorschner Michael O MO Samii Ali A Agarwal Pinky P Roberts John W JW Klepitskaya Olga O Shprecher David R DR Chung Kathryn A KA Factor Stewart A SA Espay Alberto J AJ Revilla Fredy J FJ Higgins Donald S DS Litvan Irene I Leverenz James B JB Yearout Dora D Inca-Martinez Miguel M Martinez Erica E Thompson Tiffany R TR Cholerton Brenna A BA Hu Shu-Ching SC Edwards Karen L KL Kim Kwang-Soo KS Zabetian Cyrus P CP

Molecular neurodegeneration 20150924

<h4>Objective</h4>To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD).<h4>Methods</h4>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. Cu ...[more]

PMID: 26399558

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Project description:BackgroundParkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD.MethodsAffected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed.FindingsWe found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase.InterpretationOur study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD.FundingNational Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Dataset Information

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

Publications

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

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