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

Abstract

Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2voltage-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 SNP most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus (eQTL) 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 (CCBs), we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.

A Role for Noncoding Variation in Schizophrenia

“…Furthermore, the risk variant is associated with reduced CACNA1C gene expression and transcriptional activity in the eSNP and in vitro experiments, respectively. Another recent study reported that CACNA1C rs1006737 (or rs2159100) is associated with decreased gene expression (Gershon et al, 2013), similar to our findings, although this is not consistently observed (Bigos et al, 2010). Since the initial report of CACNA1C association with bipolar disorder (Ferreira et al, 2008), there has been follow up with studies that report effects on functional connectivity in attention and emotion networks, cognitive performance and personality traits in SCZ and bipolar disorder (Bigos et al, 2010; Erk et al, 2010; Hori et al, 2012; Paulus et al, 2013; Radua et al, 2013; Roussos et al, 2013; Roussos et al, 2011; Tesli et al, 2013).…”

The Planar Cell Polarity Transmembrane Protein Vangl2 Promotes Dendrite, Spine and Glutamatergic Synapse Formation in the Mammalian Forebrain

“…This is, in fact, a well-established theme for Wnt/PCP signaling in other developmental contexts [13,46,47]. A similar phenomenon has been observed for loci contributing to neuropsychiatry through entirely different mechanisms, including ion channel proteins such as KCNA2 for which both gain- and loss-of-function mutations cause epilepsy [48] and CACNA1C for which both a gain-of-function mutation and reduced expression variants are associated with bipolar disorder [49]. This is now also firmly established for several copy number variants, such as 7q11.23 and 22q11.2, that contribute to psychiatric susceptibility either when deleted or duplicated [3,50].…”

Genetics of bipolar disorder

“…As the SNP is not located in the coding region of the gene CACNA1C , researchers have hypothesized that the variant could influence gene expression. In postmortem brain studies, scientists found evidence of reduced CACNA1C gene expression in individuals with the A allele, particularly in the cerebellum but not in other brain regions 30. However, this finding could not be replicated by other researchers, and some groups have even found increased gene expression 31.…”