A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144. Epub 2014 Nov 17.

Abstract

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Carrier Proteins / genetics
  • Conserved Sequence
  • Exome
  • Female
  • Genes, Dominant
  • Heat-Shock Proteins / genetics
  • Humans
  • Male
  • Membrane Proteins
  • Molecular Sequence Data
  • Mutation, Missense*
  • Myoclonic Epilepsies, Progressive / genetics*
  • Nerve Tissue Proteins
  • Pedigree
  • Point Mutation*
  • Prion Proteins
  • Prions / genetics
  • Protein Conformation
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Shaw Potassium Channels / genetics*
  • Shaw Potassium Channels / physiology
  • Species Specificity

Substances

  • Carrier Proteins
  • Heat-Shock Proteins
  • KCNC1 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PRNP protein, human
  • Prion Proteins
  • Prions
  • SACS protein, human
  • Shaw Potassium Channels
  • TBC1D24 protein, human