Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Molecular neurodegeneration, 2015-09, Vol.10 (1), p.50-50, Article 50

Ort / Verlag

England: BioMed Central Ltd

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). 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. 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. 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.