Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse

Cell. 1997 Feb 7;88(3):385-92. doi: 10.1016/s0092-8674(00)81877-2.


Ca2+ channel beta subunits regulate voltage-dependent calcium currents through direct interaction with alpha 1 subunits. The beta- and alpha 1-binding motifs are conserved, and all beta subunits can stimulate current amplitude, voltage dependence, and kinetics when coexpressed with various alpha 1 subunits. We used a positional candidate approach to determine that the ataxia and seizures in the lethargic (lh) mouse arise from mutation of the beta-subunit gene Cchb4 on mouse chromosome 2. A four-nucleotide insertion into a splice donor site results in exon skipping, translational frameshift, and protein truncation with loss of the alpha 1-binding site. The lethargic phenotype is the first example of a mammalian neurological disease caused by an inherited defect in a non-pore-forming subunit of a voltage-gated ion channel.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Ataxia / genetics*
  • Ataxia / metabolism*
  • Base Sequence
  • Brain / metabolism
  • Calcium Channels / genetics*
  • DNA Transposable Elements
  • Exons
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutation*
  • Organ Specificity / genetics
  • RNA Splicing
  • RNA, Messenger / biosynthesis
  • Seizures / genetics*
  • Seizures / metabolism*


  • Calcium Channels
  • DNA Transposable Elements
  • RNA, Messenger

Associated data

  • GENBANK/AF061330
  • GENBANK/AF068899
  • GENBANK/U80985
  • GENBANK/U80986