Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and glutamine transport

Brain. 2016 Dec;139(Pt 12):3109-3120. doi: 10.1093/brain/aww244. Epub 2016 Oct 14.


Progressive myoclonus epilepsy is a heterogeneous group of disorders characterized by myoclonic and tonic-clonic seizures, ataxia and cognitive decline. We here present two affected brothers. At 9 months of age the elder brother developed ataxia and myoclonic jerks. In his second year he lost the ability to walk and talk, and he developed drug-resistant progressive myoclonus epilepsy. The cerebrospinal fluid level of glutamate was decreased while glutamine was increased. His younger brother manifested similar symptoms from 6 months of age. By exome sequencing of the proband we identified a novel homozygous frameshift variant in the potassium channel tetramerization domain 7 (KCTD7) gene (NM_153033.1:c.696delT: p.F232fs), which results in a truncated protein. The identified F232fs variant is inherited in an autosomal recessive manner, and the healthy consanguineous parents carry the variant in a heterozygous state. Bioinformatic analyses and structure modelling showed that KCTD7 is a highly conserved protein, structurally similar to KCTD5 and several voltage-gated potassium channels, and that it may form homo- or heteromultimers. By heterologous expression in Xenopus laevis oocytes, we demonstrate that wild-type KCTD7 hyperpolarizes cells in a K+ dependent manner and regulates activity of the neuronal glutamine transporter SAT2 (Slc38a2), while the F232fs variant impairs K+ fluxes and obliterates SAT2-dependent glutamine transport. Characterization of four additional disease-causing variants (R94W, R184C, N273I, Y276C) bolster these results and reveal the molecular mechanisms involved in the pathophysiology of KCTD7-related progressive myoclonus epilepsy. Thus, our data demonstrate that KCTD7 has an impact on K+ fluxes, neurotransmitter synthesis and neuronal function, and that malfunction of the encoded protein may lead to progressive myoclonus epilepsy.

Keywords: BTB/POZ domain; KCTD7; Kv channel; PME; Slc38.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System A / metabolism
  • Animals
  • Biological Transport
  • Child, Preschool
  • Consanguinity
  • Fatal Outcome
  • Glutamine / metabolism*
  • Humans
  • Male
  • Myoclonic Epilepsies, Progressive / genetics*
  • Neurons / metabolism*
  • Oocytes
  • Pedigree
  • Potassium / metabolism*
  • Potassium Channels / genetics*
  • Saudi Arabia
  • Siblings
  • Xenopus laevis


  • Amino Acid Transport System A
  • KCTD7 protein, human
  • Potassium Channels
  • Slc38a2 protein, mouse
  • Glutamine
  • Potassium