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

Ignacio F. Mata, Yongwoo Jang, Chun Hyung Kim, David S. Hanna, Michael O. Dorschner, Ali Samii, Pinky Agarwal, John W. Roberts, Olga Klepitskaya, David R. Shprecher, Kathryn (Kathy) Chung, Stewart A. Factor, Alberto J. Espay, Fredy J. Revilla, Donald S. Higgins, Irene Litvan, James B. Leverenz, Dora Yearout, Miguel Inca-Martinez, Erica MartinezTiffany R. Thompson, Brenna A. Cholerton, Shu Ching Hu, Karen L. Edwards, Kwang Soo Kim, Cyrus P. Zabetian

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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.

Original languageEnglish (US)
Article number50
JournalMolecular Neurodegeneration
Volume10
Issue number1
DOIs
StatePublished - Sep 24 2015

Fingerprint

Parkinson Disease
Mutation
Exome
X-Linked Genes
Penetrance
X Chromosome
Missense Mutation
Mutant Proteins
Pedigree
Age of Onset
Computer Simulation
Genes
Cultured Cells
Genotype
Parkinson Disease 12
Phenotype
Amino Acids
Proteins

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Mata, I. F., Jang, Y., Kim, C. H., Hanna, D. S., Dorschner, M. O., Samii, A., ... Zabetian, C. P. (2015). The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. Molecular Neurodegeneration, 10(1), [50]. https://doi.org/10.1186/s13024-015-0045-4

The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. / 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 (Kathy); 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.

In: Molecular Neurodegeneration, Vol. 10, No. 1, 50, 24.09.2015.

Research output: Contribution to journalArticle

Mata, IF, Jang, Y, Kim, CH, Hanna, DS, Dorschner, MO, Samii, A, Agarwal, P, Roberts, JW, Klepitskaya, O, Shprecher, DR, Chung, KK, 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 2015, 'The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease', Molecular Neurodegeneration, vol. 10, no. 1, 50. https://doi.org/10.1186/s13024-015-0045-4
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 (Kathy) ; 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. / The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. In: Molecular Neurodegeneration. 2015 ; Vol. 10, No. 1.
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T1 - The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease

AU - Mata, Ignacio F.

AU - Jang, Yongwoo

AU - Kim, Chun Hyung

AU - Hanna, David S.

AU - Dorschner, Michael O.

AU - Samii, Ali

AU - Agarwal, Pinky

AU - Roberts, John W.

AU - Klepitskaya, Olga

AU - Shprecher, David R.

AU - Chung, Kathryn (Kathy)

AU - Factor, Stewart A.

AU - Espay, Alberto J.

AU - Revilla, Fredy J.

AU - Higgins, Donald S.

AU - Litvan, Irene

AU - Leverenz, James B.

AU - Yearout, Dora

AU - Inca-Martinez, Miguel

AU - Martinez, Erica

AU - Thompson, Tiffany R.

AU - Cholerton, Brenna A.

AU - Hu, Shu Ching

AU - Edwards, Karen L.

AU - Kim, Kwang Soo

AU - Zabetian, Cyrus P.

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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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