Identification of TMEM230 mutations in familial Parkinson's disease

Nat Genet. 2016 Jul;48(7):733-9. doi: 10.1038/ng.3589.

Han-Xiang Deng ¹, Yong Shi ¹, Yi Yang ¹, Kreshnik B Ahmeti ¹, Nimrod Miller ², Cao Huang ³, Lijun Cheng ¹, Hong Zhai ¹, Sheng Deng ¹ ⁴, Karen Nuytemans ⁵, Nicola J Corbett ⁶, Myung Jong Kim ¹, Hao Deng ⁷ ⁸, Beisha Tang ⁹ ¹⁰, Ziquang Yang ¹ ¹¹, Yanming Xu ¹², Piu Chan ¹³, Bo Huang ³, Xiao-Ping Gao ¹⁴, Zhi Song ⁸, Zhenhua Liu ⁹, Faisal Fecto ¹, Nailah Siddique ¹, Tatiana Foroud ¹⁵, Joseph Jankovic ¹⁶, Bernardino Ghetti ¹⁷, Daniel A Nicholson ⁶, Dimitri Krainc ¹, Onur Melen ¹, Jeffery M Vance ⁵, Margaret A Pericak-Vance ⁵, Yong-Chao Ma ², Ali H Rajput ¹⁸, Teepu Siddique ¹

Affiliations

1 Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
2 Departments of Pediatrics, Lurie Children's Hospital of Chicago Research Center, Northwestern University, Chicago, Illinois, USA.
3 Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
4 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
5 John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
6 Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
7 Center for Experimental Medicine, Third Xiangya Hospital, Central South University, Changsha, China.
8 Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China.
9 Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
10 National Laboratory of Medical Genetics of China, Central South University, Changsha, China.
11 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
12 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
13 Department of Neurology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China.
14 Department of Neurology, People's Hospital of Hunan Province, Changsha, China.
15 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
16 Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
17 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
18 Division of Neurology, University of Saskatchewan and Saskatoon Health Region, Saskatoon, Saskatchewan, Canada.

PMID: 27270108 DOI: 10.1038/ng.3589

Abstract

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.

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