Identification of TMEM230 mutations in familial Parkinson's disease

• Published in: Nature genetics Vol. 48; no. 7; pp. 733 - 739
• Main Authors: Deng, Han-Xiang, Shi, Yong, Yang, Yi, Ahmeti, Kreshnik B, Miller, Nimrod, Huang, Cao, Cheng, Lijun, Zhai, Hong, Deng, Sheng, Nuytemans, Karen, Corbett, Nicola J, Kim, Myung Jong, Deng, Hao, Tang, Beisha, Yang, Ziquang, Xu, Yanming, Chan, Piu, Huang, Bo, Gao, Xiao-Ping, Song, Zhi, Liu, Zhenhua, Fecto, Faisal, Siddique, Nailah, Foroud, Tatiana, Jankovic, Joseph, Ghetti, Bernardino, Nicholson, Daniel A, Krainc, Dimitri, Melen, Onur, Vance, Jeffery M, Pericak-Vance, Margaret A, Ma, Yong-Chao, Rajput, Ali H, Siddique, Teepu
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2016; Nature Publishing Group
• Subjects: 45; 45/23; 631/208/1516; 692/617/375/1718; Age; Age of Onset; Aged; Aged, 80 and over; Agriculture; Amino Acid Sequence; Animal Genetics and Genomics; Biomedicine; Cancer Research; Care and treatment; Cells, Cultured; Chromosomes; Defects; Development and progression; Female; Gene Function; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; Genomes; Genomics; Haplotypes; Health aspects; Human Genetics; Humans; Identification and classification; Male; Membrane Proteins - genetics; Microscopy; Middle Aged; Mutation; Mutation - genetics; Neurons; Neurons - metabolism; Neurons - pathology; Parkinson Disease - genetics; Parkinson's disease; Pathogenesis; Pathology; Pedigree; Properties; Protein Transport - genetics; Sequence Homology, Amino Acid; Synaptic Vesicles - metabolism; Synaptic Vesicles - pathology
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3589

Han-Xiang Deng and colleagues identify TMEM230 mutations in Lewy body–confirmed Parkinson's disease. They also show evidence that disease-associated TMEM230 mutants impair synaptic vesicle trafficking in neurons. Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body–confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.