Table 1.
Evidence for change in calcium channel function in psychiatric disorders linked with calcium channel genes.
| Disorder | Gene | Type of mutation | Gain/loss of function | Effects on calcium channel function | Reference |
|---|---|---|---|---|---|
| Schizophrenia | CACNA1B, CACNA1C, CACNA1H, CACNA1S, CACNB4, CACNA2D1,2,4 | Rare germline mutations in coding region or splice sites, mainly causing truncation (heterozygous) | Loss likely in most cases | Truncated protein/also nonsense-mediated mRNA degradation (see Fig. 2) | (Purcell et al., 2014). |
| Schizophrenia bipolar disorder autism | CACNA1C | Intronic SNPs (esp. rs1006737) subjects can be hetero- or homozygous for risk allele, A in rs1006737) | Gain | Increased mRNA expression in brain and induced neurons | (Bigos et al., 2010, Yoshimizu et al., 2015) |
| Partial loss | Reduced transcription because of reduced interaction with promoter | (Roussos et al., 2014) | |||
| Partial loss | rs1006737 and rs1024582 decreased gene expression in post-mortem cerebellum | (Gershon et al., 2014) | |||
| Timothy syndrome (includes autism) | CACNAIC | Rare germline missense point mutations | Gain | Loss of inactivation | (Splawski et al., 2004) |
| Autism | CACNA2D3 | Rare germline mutations; truncating, splice site, deletion (heterozygous) | Complete loss | Truncated protein or nonsense-mediated mRNA degradation | (De Rubeis et al., 2014, Iossifov et al., 2012, Girirajan et al., 2013) |
| CACNB2 | Rare germline point mutations in coding sequence (heterozygous but incomplete segregation with disease) | Gain and loss | Inconsistent effects on channel function | (Breitenkamp et al., 2014) | |
| CACNA1H | Rare germline point mutations in coding region (did not segregate completely with disease) | Loss | Reduced currents | (Splawski et al., 2006) | |
| CACNA1D | Rare germline point mutations in coding region | Gain | Increased currents or loss of inactivation | (Pinggera et al., 2015) | |
| Intellectual disability/hyper-aldosteronism | CACNA1D | Rare germline point mutations in coding region | Gain | Loss of inactivation or hyperpolarization of window current | (Scholl et al., 2013) |
| Intellectual disability/epilepsy | CACNA2D2 | Rare recessive point mutation | Complete loss | Loss of function of α2δ-2 to increase calcium currents | (Pippucci et al., 2013, Edvardson et al., 2013) |
| Fragile X syndrome (cognitive impairment, autism) | FMR1 | CAG repeat expansion | Loss of FMRP protein | Gain of CaV2 calcium channel function | (Ferron et al., 2014) |
| CACNA1A, B, E, G, I and CACNB1, 3 mRNAs are FMRP targets, loss of FMRP will upregulate expression | (Darnell et al., 2011) |