title: The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.
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.
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. nachofm@uw.edu.|Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. nachofm@uw.edu.
authors.forename: Ignacio F
authors.initials: IF
authors.lastname: Mata
authors.affiliation: Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. yjang@mclean.harvard.edu.
authors.forename: Yongwoo
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. chkim@mclean.harvard.edu.
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. dshanna@uw.edu.|Department of Pathology, University of Washington, Seattle, WA, USA. dshanna@uw.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Hanna
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. mod@uw.edu.|Department of Pathology, University of Washington, Seattle, WA, USA. mod@uw.edu.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Dorschner
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. asamii@uw.edu.|Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. asamii@uw.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Samii
authors.affiliation: Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA, USA. PAgarwal2@evergreenhealthcare.org.
authors.forename: Pinky
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Virginia Mason Medical Center, Seattle, WA, USA. John.Roberts@vmmc.org.
authors.forename: John W
authors.initials: JW
authors.lastname: Roberts
authors.affiliation: Department of Neurology, University of Colorado, Denver, USA. Olga.Klepitskaya@ucdenver.edu.
authors.forename: Olga
authors.initials: O
authors.lastname: Klepitskaya
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, UT, USA. David.Shprecher@hsc.utah.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Shprecher
authors.affiliation: Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, USA. chungka@ohsu.edu.|Department of Neurology, Oregon Health and Science University, Portland, OR, USA. chungka@ohsu.edu.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Chung
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA. sfactor@emory.edu.
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Factor
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA. espayaj@ucmail.uc.edu.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Espay
authors.affiliation: Division of Neurology at Greenville Health System and the University of South Carolina Medical School-Greenville, Greenville, SC, USA. revillf@gmail.com.
authors.forename: Fredy J
authors.initials: FJ
authors.lastname: Revilla
authors.affiliation: Samuel Stratton Veterans Affairs Medical Center, Albany, NY, USA. higgind@mail.amc.edu.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Higgins
authors.affiliation: Movement Disorder Center, Department of Neurosciences, University of California, San Diego, CA, USA. ilitvan@ucsd.edu.
authors.forename: Irene
authors.initials: I
authors.lastname: Litvan
authors.affiliation: Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA. leverej@ccf.org.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. doray@uw.edu.|Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. doray@uw.edu.
authors.forename: Dora
authors.initials: D
authors.lastname: Yearout
authors.affiliation: Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru. miguel.inca.martinez@gmail.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: Inca-Martinez
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. ekovak@uw.edu.|Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. ekovak@uw.edu.
authors.forename: Erica
authors.initials: E
authors.lastname: Martinez
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. iamtiff@uw.edu.
authors.forename: Tiffany R
authors.initials: TR
authors.lastname: Thompson
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. bchol@uw.edu.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. bchol@uw.edu.
authors.forename: Brenna A
authors.initials: BA
authors.lastname: Cholerton
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. shuching@uw.edu.|Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. shuching@uw.edu.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hu
authors.affiliation: Department of Epidemiology, University of California, Irvine, CA, USA. kedward1@uci.edu.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Edwards
authors.affiliation: Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. kskim@mclean.harvard.edu.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. zabetian@u.washington.edu.|Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. zabetian@u.washington.edu.
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
mesh_terms: D000328:Adult; D017668:Age of Onset; D000818:Animals; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D010641:Phenotype; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: C547812:Rab39B protein, human; D020691:rab GTP-Binding Proteins