Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome

J Mol Cell Cardiol. 2015 Mar;80:186-95. doi: 10.1016/j.yjmcc.2015.01.002. Epub 2015 Jan 26.


Gain-of-function mutations in CACNA1C, encoding the L-type Ca(2+) channel Cav1.2, cause Timothy syndrome (TS), a multi-systemic disorder with dysmorphic features, long-QT syndrome (LQTS) and autism spectrum disorders. TS patients have heterozygous mutations (G402S and G406R) located in the alternatively spliced exon 8, causing a gain-of-function by reduced voltage-dependence of inactivation. Screening 540 unrelated patients with non-syndromic forms of LQTS, we identified six functional relevant CACNA1C mutations in different regions of the channel. All these mutations caused a gain-of-function combining different mechanisms, including changes in current amplitude, rate of inactivation and voltage-dependence of activation or inactivation, similar as in TS. Computer simulations support the theory that the novel CACNA1C mutations prolong action potential duration. We conclude that genotype-negative LQTS patients should be investigated for mutations in CACNA1C, as a gain-of-function in Cav1.2 is likely to cause LQTS and only specific and rare mutations, i.e. in exon 8, cause the multi-systemic TS.

Keywords: Arrhythmia; Cav1.2; Gain-of-function; LQT8; Timothy syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adolescent
  • Adult
  • Amino Acid Substitution
  • Autistic Disorder / genetics
  • Calcium Channels, L-Type / chemistry
  • Calcium Channels, L-Type / genetics*
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling
  • Cell Line
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Electrocardiography
  • Female
  • Gene Expression
  • Genetic Variation
  • Humans
  • Infant
  • Long QT Syndrome / diagnosis
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / physiopathology*
  • Male
  • Mutation*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Protein Interaction Domains and Motifs
  • Syndactyly / genetics
  • Young Adult


  • CACNA1C protein, human
  • Calcium Channels, L-Type

Supplementary concepts

  • Timothy syndrome