Identification of TMEM230 mutations in familial Parkinson's disease.
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.
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Han-Xiang
HX
Deng
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Yong
Y
Shi
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Yi
Y
Yang
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Kreshnik B
KB
Ahmeti
Departments of Pediatrics, Lurie Children's Hospital of Chicago Research Center, Northwestern University, Chicago, Illinois, USA.
Nimrod
N
Miller
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Cao
C
Huang
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Lijun
L
Cheng
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Hong
H
Zhai
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
Sheng
S
Deng
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Karen
K
Nuytemans
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
Nicola J
NJ
Corbett
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Myung Jong
MJ
Kim
Center for Experimental Medicine, Third Xiangya Hospital, Central South University, Changsha, China.|Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China.
Hao
H
Deng
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.|National Laboratory of Medical Genetics of China, Central South University, Changsha, China.
Beisha
B
Tang
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
Ziquang
Z
Yang
Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
Yanming
Y
Xu
Department of Neurology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China.
Piu
P
Chan
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Bo
B
Huang
Department of Neurology, People's Hospital of Hunan Province, Changsha, China.
Xiao-Ping
XP
Gao
Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China.
Zhi
Z
Song
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Zhenhua
Z
Liu
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Faisal
F
Fecto
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Nailah
N
Siddique
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Tatiana
T
Foroud
Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
Joseph
J
Jankovic
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Bernardino
B
Ghetti
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
Daniel A
DA
Nicholson
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Dimitri
D
Krainc
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Onur
O
Melen
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Jeffery M
JM
Vance
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Margaret A
MA
Pericak-Vance
Departments of Pediatrics, Lurie Children's Hospital of Chicago Research Center, Northwestern University, Chicago, Illinois, USA.
Yong-Chao
YC
Ma
Division of Neurology, University of Saskatchewan and Saskatoon Health Region, Saskatoon, Saskatchewan, Canada.
Ali H
AH
Rajput
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Teepu
T
Siddique
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D021381:Protein Transport / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013572:Synaptic Vesicles / Q000378:metabolism / Q000473:pathology*
D008565:Membrane Proteins; C000622360:TMEM230 protein, human