Format

Send to

Choose Destination
Mol Neurodegener. 2015 Sep 24;10:50. doi: 10.1186/s13024-015-0045-4.

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

Author information

1
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. nachofm@uw.edu.
2
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. nachofm@uw.edu.
3
Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. yjang@mclean.harvard.edu.
4
Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. chkim@mclean.harvard.edu.
5
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. dshanna@uw.edu.
6
Department of Pathology, University of Washington, Seattle, WA, USA. dshanna@uw.edu.
7
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. mod@uw.edu.
8
Department of Pathology, University of Washington, Seattle, WA, USA. mod@uw.edu.
9
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. asamii@uw.edu.
10
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. asamii@uw.edu.
11
Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA, USA. PAgarwal2@evergreenhealthcare.org.
12
Virginia Mason Medical Center, Seattle, WA, USA. John.Roberts@vmmc.org.
13
Department of Neurology, University of Colorado, Denver, USA. Olga.Klepitskaya@ucdenver.edu.
14
Department of Neurology, University of Utah, Salt Lake City, UT, USA. David.Shprecher@hsc.utah.edu.
15
Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, USA. chungka@ohsu.edu.
16
Department of Neurology, Oregon Health and Science University, Portland, OR, USA. chungka@ohsu.edu.
17
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA. sfactor@emory.edu.
18
Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA. espayaj@ucmail.uc.edu.
19
Division of Neurology at Greenville Health System and the University of South Carolina Medical School-Greenville, Greenville, SC, USA. revillf@gmail.com.
20
Samuel Stratton Veterans Affairs Medical Center, Albany, NY, USA. higgind@mail.amc.edu.
21
Movement Disorder Center, Department of Neurosciences, University of California, San Diego, CA, USA. ilitvan@ucsd.edu.
22
Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA. leverej@ccf.org.
23
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. doray@uw.edu.
24
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. doray@uw.edu.
25
Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru. miguel.inca.martinez@gmail.com.
26
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. ekovak@uw.edu.
27
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. ekovak@uw.edu.
28
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. iamtiff@uw.edu.
29
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. bchol@uw.edu.
30
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. bchol@uw.edu.
31
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. shuching@uw.edu.
32
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. shuching@uw.edu.
33
Department of Epidemiology, University of California, Irvine, CA, USA. kedward1@uci.edu.
34
Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. kskim@mclean.harvard.edu.
35
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. zabetian@u.washington.edu.
36
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. zabetian@u.washington.edu.

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.

PMID:
26399558
PMCID:
PMC4581468
DOI:
10.1186/s13024-015-0045-4
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center