Mutations in the Scn8a DIIS4 voltage sensor reveal new distinctions among hypomorphic and null Na v 1.6 sodium channels

Genes Brain Behav. 2020 Apr;19(4):e12612. doi: 10.1111/gbb.12612. Epub 2019 Oct 28.

Abstract

Mutations in the voltage-gated sodium channel gene SCN8A cause a broad range of human diseases, including epilepsy, intellectual disability, and ataxia. Here we describe three mouse lines on the C57BL/6J background with novel, overlapping mutations in the Scn8a DIIS4 voltage sensor: an in-frame 9 bp deletion (Δ9), an in-frame 3 bp insertion (∇3) and a 35 bp deletion that results in a frameshift and the generation of a null allele (Δ35). Scn8a Δ9/+ and Scn8a ∇3/+ heterozygous mutants display subtle motor deficits, reduced acoustic startle response, and are resistant to induced seizures, suggesting that these mutations reduce activity of the Scn8a channel protein, Nav 1.6. Heterozygous Scn8a Δ35/+ mutants show no alterations in motor function or acoustic startle response, but are resistant to induced seizures. Homozygous mutants from each line exhibit premature lethality and severe motor impairments, ranging from uncoordinated gait with tremor (Δ9 and ∇3) to loss of hindlimb control (Δ35). Scn8a Δ9/Δ9 and Scn8a ∇3/∇3 homozygous mutants also exhibit impaired nerve conduction velocity, while normal nerve conduction was observed in Scn8a Δ35/Δ35 homozygous mice. Our results suggest that hypomorphic mutations that reduce Nav 1.6 activity will likely result in different clinical phenotypes compared to null alleles. These three mouse lines represent a valuable opportunity to examine the phenotypic impacts of hypomorphic and null Scn8a mutations without the confound of strain-specific differences.

Keywords: Scn8a; Nav1.6; clinical spectrum; hypomorphic allele; motor deficit; nerve conduction; null allele; seizures; sodium channel; voltage sensor.

Publication types

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

MeSH terms

  • Action Potentials
  • Animals
  • Homozygote
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Movement*
  • Mutation*
  • NAV1.6 Voltage-Gated Sodium Channel / chemistry
  • NAV1.6 Voltage-Gated Sodium Channel / genetics*
  • Phenotype
  • Protein Domains

Substances

  • NAV1.6 Voltage-Gated Sodium Channel
  • Scn8a protein, mouse