- 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
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.