Identification of candidate genes for familial early-onset essential tremor

Eur J Hum Genet. 2016 Jul;24(7):1009-15. doi: 10.1038/ejhg.2015.228. Epub 2015 Oct 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Endopeptidases / genetics
  • Essential Tremor / genetics*
  • Essential Tremor / pathology
  • Extracellular Matrix Proteins / genetics
  • Female
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Nerve Tissue Proteins / genetics
  • Nitric Oxide Synthase Type III / genetics*
  • Pedigree
  • Potassium Channels, Voltage-Gated / genetics

Substances

  • Extracellular Matrix Proteins
  • HAPLN4 protein, human
  • KCNS2 protein, human
  • Nerve Tissue Proteins
  • Potassium Channels, Voltage-Gated
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Endopeptidases
  • ubiquitin-specific peptidase 46, human