L‐type calcium channels and psychiatric disorders: A brief review

Casamassima, Francesco; Hay, Aleena C.; Benedetti, Alessandra; Lattanzi, Lorenzo; Cassano, Giovanni Battista; Perlis, Roy H.

doi:10.1002/ajmg.b.31122

Cited by 115 publications

(101 citation statements)

References 229 publications

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“…Given the strategic roles of Ca V 1.2, and the high penetrance of the TS mutation in causing autism, it is both striking and reassuring that we were able to observe a full triad of autism-related behaviors in our mice. The critical importance of Ca V 1.2 channels may also be reflected in its involvement in other psychiatric diseases, like bipolar disorder and, potentially, substance abuse and dependence (29). Our behavioral approaches set the stage for future studies to explore altered brain circuits underlying the behavioral traits described here, and to determine whether the various behaviors can be modified by L-type channel blockers, either by early intervention or acute treatment.…”

Section: Discussionmentioning

confidence: 99%

Mouse model of Timothy syndrome recapitulates triad of autistic traits

Bader

Faizi²,

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

182

203

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Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca V 1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca V 1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tonecued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.utism and autism spectrum disorder (ASD) are characterized by the concomitant occurrence of impaired social interaction; restricted, perseverative, and stereotypical behavior; and abnormal communication skills (1). However, the etiology remains largely unknown, in large part because most cases of ASD arise from a mixture of multiple environmental and multiple genetic influences (2), making it difficult to forge causal links to behavior. In the face of such complexity, insights might be gleaned from simple forms of ASD, generated by single, highly penetrant mutations. Timothy syndrome (TS), is a rare disorder strongly associated with autism or ASD (penetrance w75%; P = 1.2 × 10 −8 ). Other symptoms of TS include long QT syndrome, webbed fingers and toes, dysmorphic facial features, and immunodeficiency (3). Importantly, Splawski et al. (3) traced the disease to a single nucleotide mutation in the gene encoding the pore-forming subunit of an L-type calcium channel (Ca V 1.2). This sporadic glycine-to-arginine mutation is located at position 406 in exon 8A [Splawski's terminology (3), VNDAV-coding exon, low (w20%) expression in brain and heart]. If a Gly-toArg mutation occurs in the more highly (w80%) expressed (4) alternative exon 8 (MQDAM-coding exon, 59 of exon 8A) it causes a more severe variant of TS (TS2). In heterologous expression ...

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Section: Discussionmentioning

confidence: 99%

Mouse model of Timothy syndrome recapitulates triad of autistic traits

Bader

Faizi²,

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

182

203

View full text Add to dashboard Cite

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“…Subunits encoded by CACNA1C and CACNA1D are the only L-type subunits that play a significant role in neuronal functioning which includes neurotransmitter release and changes in gene expression [24]. Alterations in calcium signaling have been indirectly implicated in BPI [25]. Calcium channel blockers - which bind to L-type channels - have been used with mixed success in the treatment of BPI, but the clinical trials have all involved a small number of subjects and thus have been underpowered.…”

Section: Discussionmentioning

confidence: 99%

A Rare Variant in <b><i>CACNA1D</i></b> Segregates with 7 Bipolar I Disorder Cases in a Large Pedigree

et al. 2016

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Whole-genome sequencing was performed on 3 bipolar I disorder (BPI) cases from a multiplex pedigree of European ancestry with 7 BPI cases. Within CACNA1D, a gene implicated by genome-wide association studies, a G to C nucleotide transversion at 53,835,340 base pairs (bps) was found predicting the substitution of proline for alanine at amino acid position 1751 (A1751P). Using Sanger sequencing, the DNA variant was shown to co-segregate with the remaining 4 BPI cases within the pedigree. A high-resolution DNA denaturing curve method was then used to screen for the presence of the A1751P change in 4,150 BPI cases from the NIMH Genetics Initiative. The A1751P variant was found in 4 BPI cases. A second variant within exon 43, a C to T nucleotide transition, was found in 1 case at 53,835,355 bps, predicting the substitution of tryptophan for arginine at amino acid position 1771 (R1771W). In the NHLBI Exome Sequencing Project database, the heterozygous A1751P variant was present in 3 of 4,300 subjects of European ancestry, and the R1771W change was not present in any subject. Given the rarity of these variants, large-scale case/control rare variant sequencing studies will be required for definitive conclusions.

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“…22 Accordingly, genetic studies suggest that the pathobiology of schizophrenia involves various voltage-gated ion channels. [28][29][30] Because these proteins also control cardiac electrophysiology, variants in their encoding genes (KCNH2, CACNA1C) may increase arrhythmia and SCD risk. We did not screen KCNH2 and CACNA1C in the patients with Brugada-ECG, but only SCN5A, because SCN5A is the only gene routinely screened at our institution in BrS patients.…”

Section: Schizophrenia and Brugada-ecgmentioning

confidence: 99%

Brugada Syndrome ECG Is Highly Prevalent in Schizophrenia

Blom

Cohen

Seldenrijk

et al. 2014

Circ: Arrhythmia and Electrophysiology

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Background— The causes of increased risk of sudden cardiac death in schizophrenia are not resolved. We aimed to establish (1) whether ECG markers of sudden cardiac death risk, in particular Brugada-ECG pattern, are more prevalent among patients with schizophrenia, and (2) whether increased prevalence of these ECG markers in schizophrenia is explained by confounding factors, notably sodium channel–blocking medication. Methods and Results— In a cross-sectional study, we analyzed ECGs of a cohort of 275 patients with schizophrenia, along with medication use. We determined whether Brugada-ECG was present and assessed standard ECG measures (heart rate, PQ-, QRS-, and QT-intervals). We compared the findings with nonschizophrenic individuals of comparable age (the Netherlands Study of Depression and Anxiety [NESDA] cohort; N=179) and, to account for assumed increased aging rate in schizophrenia, with individuals 20 years older (Hoorn cohort; n=1168), using multivariate regression models. Brugada-ECG was significantly more prevalent in the schizophrenia cohort (11.6%) compared with NESDA controls (1.1%) or Hoorn controls (2.4%). Moreover, patients with schizophrenia had longer QT-intervals (410.9 versus 393.1 and 401.9 ms; both P <0.05), increased proportion of mild or severe QTc prolongation (13.1% and 5.8% versus 3.4% and 0.0% [NESDA], versus 5.1 and 2.8% [Hoorn]), and higher heart rates (80.8 versus 61.7 and 68.0 beats per minute; both P <0.05). The prevalence of Brugada-ECG was still increased (9.6%) when patients with schizophrenia without sodium channel–blocking medication were compared with either of the control cohorts. Conclusions— Brugada-ECG has increased prevalence among patients with schizophrenia. This association is not explained by the use of sodium channel–blocking medication.

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L‐type calcium channels and psychiatric disorders: A brief review

Cited by 115 publications

References 229 publications

Mouse model of Timothy syndrome recapitulates triad of autistic traits

Mouse model of Timothy syndrome recapitulates triad of autistic traits

A Rare Variant in <b><i>CACNA1D</i></b> Segregates with 7 Bipolar I Disorder Cases in a Large Pedigree

Brugada Syndrome ECG Is Highly Prevalent in Schizophrenia

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