A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain

Mol Psychiatry. 2014 Aug;19(8):890-4. doi: 10.1038/mp.2013.107. Epub 2013 Aug 27.


Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2 voltage-gated calcium channels during cellular action potentials, with greatly increased influx of calcium into the activated cells. The major clinical feature of this syndrome is a long QT interval that results in cardiac arrhythmias. However, TS also includes cognitive impairment, autism and major developmental delays in many of the patients. We observed the appearance of bipolar disorder (BD) in a patient with a previously reported case of TS, who is one of the very few patients to survive childhood. This is most interesting because the common single-nucleotide polymorphism (SNP) most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus for CACNA1C in human cerebellum, and the risk allele (A) is associated with decreased expression. To combine the CACNA1C perturbations in the presence of BD in this patient and in patients with the common CACNA1C SNP risk allele, we would propose that either increase or decrease in calcium influx in excitable cells can be associated with BD. In treatment of BD with calcium channel blocking drugs, we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.

Publication types

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

MeSH terms

  • Adult
  • Autistic Disorder
  • Bipolar Disorder / complications
  • Bipolar Disorder / genetics*
  • Brain / metabolism*
  • Calcium Channels, L-Type / biosynthesis
  • Calcium Channels, L-Type / genetics*
  • Cerebellum / metabolism
  • Down-Regulation / genetics*
  • Gene Expression Profiling
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Long QT Syndrome / complications
  • Long QT Syndrome / genetics
  • Male
  • Mutation / genetics*
  • Parietal Lobe / metabolism
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci / genetics
  • Syndactyly / complications
  • Syndactyly / genetics


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

Supplementary concepts

  • Timothy syndrome