TY - JOUR
T1 - Identification of candidate genes for familial early-onset essential tremor
AU - Liu, Xinmin
AU - Hernandez, Nora
AU - Kisselev, Sergey
AU - Floratos, Aris
AU - Sawle, Ashley
AU - Ionita-Laza, Iuliana
AU - Ottman, Ruth
AU - Louis, Elan D.
AU - Clark, Lorraine N.
N1 - Funding Information:
Dr Louis has received research support from the National Institutes of Health (NIH): NINDS #R01 NS042859 (principal investigator), NINDS #R01 NS39422 (principal investigator), NINDS #R01 NS086736 (principal investigator), NINDS #R01 NS073872 (principal investigator), NINDS #R01 NS085136 (principal investigator) and NINDS #R01 NS088257 (principal investigator). Dr Clark is funded by NIH grants R21NS050487 (PI), R01NS060113 (PI), R01NS0738072 (CoPI), P50AG008702 (CoI), P50 NS038370 (CoI), the Parkinson's disease foundation (PI) and the Michael J Fox foundation (CoI). Dr Ottman is funded by NINDS #R01 NS078419 (PI), #U01 NS077276 (MPI), #U01 NS077367 (MPI), #NIH R01 NS073872 (CoI), NHGRI #P50 HG007257 (CoI), and NIA #R01 AG041797 (CoI). We thank the patients and families for participating in this study. We like to acknowledge and thank Drs Peter Nagy and Jane Dunning Broadbent for performing the sequencing at the clinical NGS core, laboratory of personalized medicine, at Columbia University.
Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.46G4A (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.164C4T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved aminoacid 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.
AB - 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.46G4A (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.164C4T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved aminoacid 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.
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U2 - 10.1038/ejhg.2015.228
DO - 10.1038/ejhg.2015.228
M3 - Article
C2 - 26508575
AN - SCOPUS:84945576291
VL - 24
SP - 1009
EP - 1015
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 7
ER -