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

  • Author(s): Mata, IF
  • Jang, Y
  • Kim, CH
  • Hanna, DS
  • Dorschner, MO
  • Samii, A
  • Agarwal, P
  • Roberts, JW
  • Klepitskaya, O
  • Shprecher, DR
  • Chung, KA
  • Factor, SA
  • Espay, AJ
  • Revilla, FJ
  • Higgins, DS
  • Litvan, I
  • Leverenz, JB
  • Yearout, D
  • Inca-Martinez, M
  • Martinez, E
  • Thompson, TR
  • Cholerton, BA
  • Hu, SC
  • Edwards, KL
  • Kim, KS
  • Zabetian, CP
  • et al.
Abstract

© 2015 Mata et al. 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.

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