Research progress on phenotype and mechanism of cardiac disease caused by CACNA1C gene mutations / 中华实用儿科临床杂志

Mutations in the CACNA1C gene which encodes the α1C subunit of voltage dependent l-type Ca2+ channel can cause mental and cardiovascular diseases.It is the pathogenic gene of Timothy syndrome.Its cardiovascular-system phenotype mainly includes long QT syndrome, Brugada syndrome, short QT syndrome, etc.In recent years, it has been found that CACNA1C gene mutations can also lead to non-syndromic phenotypes, including congenital heart disease, cardiomyopathy, etc, further enriching the clinical phenotype of CACNA1C gene mutation.Now, the recent advances in heart disease phenotypes and mechanisms involved in CACNA1C gene mutations are reviewed.

Genes Involved in Neurodevelopment, Neuroplasticity and Major Depression: No Association for CACNA1C, CHRNA7 and MAPK1

OBJECTIVE: Genetics factors are likely to play a role in the risk, clinical presentation and treatment outcome in major depressive disorder (MDD). In this study, we investigated the role of three candidate genes for MDD; calcium voltage-gated channel subunit alpha1 C (CACNA1C), cholinergic receptor nicotinic alpha 7 subunit (CHRNA7), and mitogen-activated protein kinase 1 (MAPK1). METHODS: Two-hundred forty-two MDD patients and 326 healthy controls of Korean ancestry served as samples for the analyses. Thirty-nine single nucleotide polymorphisms (SNPs) within CACNA1C, CHRNA7, and MAPK1 genes were genotyped and subsequently tested for association with MDD (primary analysis) and other clinical features (symptoms’ severity, age of onset, history of suicide attempt, treatment outcome) (secondary analyses). Single SNPs, haplotypes and epistatic analyses were performed. RESULTS: Single SNPs were not associated with disease risk and clinical features. However, a combination of alleles (haplotype) within MAPK1 was found associated with MDD-status. Secondary analyses detected a possible involvement of CACNA1C haplotype in resistance to antidepressant treatment. CONCLUSION: These data suggest a role for MAPK1 and CACNA1C in MDD risk and treatment resistance, respectively. However, since many limitations characterize the analysis, the results must be considered with great caution and verified.

Research progress on phenotype and mechanism of cardiac disease caused by CACNA1C gene mutations / 中华实用儿科临床杂志

Mutations in the CACNA1 C gene which encodes the α1 C subunit of voltage dependent Ⅰ-type Ca2 + channel can cause mental and cardiovascular diseases.It is the pathogenic gene of Timothy syndrome.Its cardiovascular-system phenotype mainly includes long QT syndrome,Brugada syndrome,short QT syndrome,etc.In recent years,it has been found that CACNA1C gene mutations can also lead to non-syndromic phenotypes,including congenital heart disease,cardiomyopathy,etc,further enriching the clinical phenotype of CACNA1C gene mutation.Now,the recent advances in heart disease phenotypes and mechanisms involved in CACNA1C gene mutations are reviewed.

Association between a Genetic Variant of CACNA1C and the Risk of Schizophrenia and Bipolar I Disorder Across Diagnostic Boundaries / 대한정신분열병학회지

OBJECTIVES: Genome-wide association studies (GWASs) and meta-analyses indicate that single-nucleotide polymorphisms (SNPs) in the a-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) gene increase the risk for schizophrenia and bipolar disorders (BDs). We investigated the association between the genetic variants on CACNA1C and schizophrenia and/or BDs in the Korean population. METHODS: A total of 582 patients with schizophrenia, 336 patients with BDs consisting of 179 bipolar I disorder (BD-I) and 157 bipolar II disorder (BD-II), and 502 healthy controls were recruited. Based on previous results from other populations, three SNPs (rs10848635, rs1006737, and rs4765905) were selected and genotype-wise association was evaluated using logistic regression analysis under additive, dominant and recessive genetic models. RESULTS: rs10848635 showed a significant association with schizophrenia (p=0.010), the combined schizophrenia and BD group (p=0.018), and the combined schizophrenia and BD-I group (p=0.011). The best fit model was dominant model for all of these phenotypes. The association remained significant after correction for multiple testing in schizophrenia and the combined schizophrenia and BD-I group. CONCLUSION: We identified a possible role of CACNA1C in the common susceptibility of schizophrenia and BD-I. However no association trend was observed for BD-II. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.

Genome-Wide Supported Risk Variants in MIR137, CACNA1C, CSMD1, DRD2, and GRM3 Contribute to Schizophrenia Susceptibility in Pakistani Population

OBJECTIVE: Schizophrenia is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide. Recently, MIR137, CACNA1C, CSMD1, DRD2, and GRM3 have been reported as the most robustly emerging candidates involved in the etiology of schizophrenia. In this case control study, we performed an association analysis of rs1625579 (MIR137), rs1006737, rs4765905 (CACNA1C), rs10503253 (CSMD1), rs1076560 (DRD2), rs12704290, rs6465084, and rs148754219 (GRM3) in Pakistani population. METHODS: Schizophrenia was diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders 4th ed (DSM-IV). Detailed clinical information, family history of all patients and healthy controls were collected. RFLP based case control association study was performed in a Pakistani cohort of 508 schizophrenia patients and 300 healthy control subjects. Alleles and genotype frequencies were calculated using SPSS. RESULTS: A significant difference in the genotype and allele frequencies for rs4765905, rs1076560 and rs6465084 were found between the patients and controls (p=0.000). CONCLUSION: This study provides substantial evidence supporting the role of CACNA1C, GRM3 and DRD2 as schizophrenia susceptibility genes in Pakistani population.

Relationship of CACNA1C gene polymorphism with schizophrenia / 中国神经精神疾病杂志

Objective To examine the relationship of calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNAIC) gene polymorphism with schizophrenia. Method A total of 118 patients with schizophrenia and 122 healthy volunteers were selected in succession. Denaturing high performance liquid chromatography (DHPLC) was used to analyze the genotypes of CACNAIC gene (rs10848683, rs2238032 and rs2299661). Medical record data of patients with schizophre?nia and the clinical manifestation of the patients (sensation and perception disorder, thought disorder, affective disorder and behavior disorder) were collected. The clinical phenotype databases of all patients were established. Result There were statistical differences for genotype and allele distribution of the rs2238032 and rs2299661 between patient group and control group (P<0.05). The TT genotype of rs2238032 (OR=0.394) and the CG genotype of rs2299661 (OR=0.326) associ?ated with the risk of schizophrenia. The genotype distribution of rs2238032 was related to the thought disorder, the emotion disorder and the PANSS score of schizophrenia patients (all P<0.05). The genotype distribution of rs2299661 was related to the perceptual disorders and PANSS score of schizophrenia patients (all P<0.05). Haplotype analysis showed that CTC (OR=1.811), CTG (OR=0.432) and TGC (OR=1.771) were significantly associated with schizophrenia (P<0.05). Conclu?sion The CACNA1C gene polymorphism is associated with schizophrenia and its clinical manifestations.

Association of CACNA1C Variants with Bipolar Disorder in the Korean Population

OBJECTIVE: Previous studies have suggested an association between CACNA1C and susceptibility of bipolar disorder. In this study, we examined the association of CACNA1C variants with bipolar disorder in the Korean population. METHODS: We selected 2 CACNA1C single nucleotide polymorphisms (SNPs), namely, rs723672 and rs1051375, based on their functions and minor allele frequencies described in previous studies. Genotypes of these 2 SNPs were analyzed by extracting DNA from blood samples collected from 287 patients with bipolar disorder and 340 healthy controls. RESULTS: Genotype frequencies of both rs723672 and rs1051375 SNPs were significantly different in patients and controls (p=0.0462 and 1.732E-14, respectively). Dominant, recessive, and allele models showed significant differences between patients and controls with respect to the rs1051375 SNP (p=1.72E-11, 4.17E-10, 4.95E-16, respectively). CONCLUSION: Our results suggested that CACNA1C SNPs rs723672 and rs1051375 were associated with bipolar disorder in the Korean population. In addition, our results highlighted the importance of CACNA1C in determining susceptibility to bipolar disorder.