Abstract
ObjectiveTo identify the causal gene in a multi-incident U.S. kindred with Parkinson’s disease (PD).MethodsWe 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0045-4) contains supplementary material, which is available to authorized users.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and though approximately 20 % of patients report a family history of the disease, kindreds that display clear Mendelian inheritance are rare
In this study we present data from with atypicalWhole-exome sequencing (WES) and in vitro functional analyses that demonstrate that a missense mutation (p.G192R) in the RAB39B gene is the causative variant in a multi-incident family with clinically typical PD
We filtered out all variants with a frequency >1 % in 515 controls from the NHLBI Exome Sequencing Project [6, 7] or that failed to meet the quality thresholds of the Genome Analysis ToolKit (GATK) “Best Practices” [8]
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and though approximately 20 % of patients report a family history of the disease, kindreds that display clear Mendelian inheritance are rare. Mutations in several genes have been shown to result in clinically typical autosomal dominant (SNCA, LRRK2, VPS35, DNAJC13) or recessive (PARK2, PINK1, PARK7) PD, or parkinsonism with atypical. Whole-exome sequencing (WES) is a powerful tool for gene discovery in pedigrees that are not sufficiently large for traditional linkage analysis [2] and this technique has been successful in identifying two causal genes for PD [3, 4]. In this study we present data from WES and in vitro functional analyses that demonstrate that a missense mutation (p.G192R) in the RAB39B gene is the causative variant in a multi-incident family with clinically typical PD.
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