Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy

Elife. 2020 May 19:9:e57190. doi: 10.7554/eLife.57190.

Abstract

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two de novo heterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulfate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients.

Keywords: TRPM3; developmental and epileptic encephalopathies; human; neuroscience; trp channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epilepsy / genetics*
  • Epilepsy / metabolism
  • Gain of Function Mutation*
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Ion Channel Gating
  • Mutation, Missense*
  • TRPM Cation Channels / genetics*
  • TRPM Cation Channels / metabolism

Substances

  • TRPM Cation Channels
  • TRPM3 protein, human