Identification of candidate genes for familial early-onset essential tremor.
Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts l-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G>A (p.(Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C>T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved amino-acid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone.
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Xinmin
X
Liu
Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.|Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
Nora
N
Hernandez
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Sergey
S
Kisselev
Department of Biomedical Informatics, Columbia University, New York, NY, USA.|Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
Aris
A
Floratos
Department of Biomedical Informatics, Columbia University, New York, NY, USA.|Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
Ashley
A
Sawle
Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.
Iuliana
I
Ionita-Laza
G.H Sergievsky Center, Columbia University, New York, NY, USA.|Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.|Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
Ruth
R
Ottman
Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.|Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
Elan D
ED
Louis
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Lorraine N
LN
Clark
D000328:Adult; D017668:Age of Onset; D010450:Endopeptidases / Q000235:genetics; D020329:Essential Tremor / Q000235:genetics* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D000099249:Proteoglycan Link Protein
D010450:Endopeptidases; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D052250:Nitric Oxide Synthase Type III; D024642:Potassium Channels, Voltage-Gated; C480571:HAPLN4 protein, human; D000099249:Proteoglycan Link Protein; C000621465:KCNS2 protein, human; C496314:NOS3 protein, human; C562185:ubiquitin-specific peptidase 46, human