L型钙离子通道α1C亚基基因多态性与精神分裂症的相关性

目的探讨L型钙离子通道α1C亚基(calcium channel,voltage-dependent,L type,alpha 1C subunit,CACNA1C)基因多态性与精神分裂症的关系。方法纳入118例精神分裂症患者及122名对照,采用变性高效液相色谱法对其CACNA1C基因rs10848683、rs2238032、rs2299661位点进行基因分型,通过病历资料收集患者感知觉障碍、思维障碍、情感障碍和行为障碍等临床表现,采用阳性与阴性症状量表(positive and negative syndrome scale,PANSS)评估患者症状。结果 rs2238032和rs2299661位点基因型和等位基因在患者组与对照组间分布有统计学差异(均P0.05),而rs10848683位点基因型和等位基因分布在组间无统计学差异(P0.05)。rs2238032位点TT基因型(OR=0.394)和rs2299661位点CG(OR=0.326)与精神分裂症的患病风险有关联(均P0.05)。rs10848683位点各基因型患者行为障碍分布有统计学差异(P0.05);rs2238032各基因型患者思维障碍、情感障碍和PANSS得分有统计学差异(均P0.05);rs2299661各基因型患者感知觉障碍、PANSS得分有统计学差异(均P0.05)。单体型分析示,CTC(OR=1.811)、CTG(OR=0.432)和TGC(OR=1.771)与精神分裂症关联有统计学意义(P0.05)。结论 CACNA1C基因多态性与精神分裂症及其临床表现有关联。     

CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: A case report

We report a one-year-old boy with early-onset myoclonic epilepsy, developmental arrest, and hyperekplexia during early infancy. He presented with refractory myoclonic/tonic seizures since birth. Electroencephalography revealed multifocal spikes, and rhythmic activities that occurred simultaneous with aggravation of myoclonus accompanied by tonic upper limb elevation. Brain magnetic resonance imaging revealed progressive cerebral atrophy with periventricular signal change and thin corpus callosum at one year of age. A de novo heterozygous missense mutation in the CACNA1A gene was confirmed. This patient was the most severe phenotype of CACNA1A-related early-onset encephalopathy among previous reports.     

CACNA1C SNP rs1006737 associates with bipolar I disorder independent of the Bcl-2 SNP rs956572 variant and its associated effect on intracellular calcium homeostasis

Objectives. Intracellular calcium (Ca²⁺) dyshomeostasis (ICDH) has been implicated in bipolar disorder (BD) pathophysiology. We previously showed that SNP rs956572 in the B-cell CLL/lymphoma 2 (Bcl-2) gene associates with elevated B lymphoblast (BLCL) intracellular Ca²⁺ concentrations ([Ca²⁺]_B) differentially in BD-I. Genome-wide association studies strongly support the association between BD and the SNP rs1006737, located within the L-type voltage-dependent Ca²⁺ channel α1C subunit gene (CACNA1C). Here we investigated whether this CACNA1C variant also associates with ICDH and interacts with SNP rs956572 on [Ca²⁺]_B in BD-I. Methods. CACNA1C SNP rs1006737 was genotyped in 150 BD-I, 65 BD-II, 30 major depressive disorder patients, and 70 healthy subjects with available BLCL [Ca²⁺]_B and Bcl-2 SNP rs956572 genotype measures. Results. SNP rs1006737 was significantly associated with BD-I. The [Ca²⁺]_B was significantly higher in BD-I rs1006737 A compared with healthy A allele carriers and also in healthy GG compared with A allele carriers. There was no significant interaction between SNP rs1006737 and SNP rs956572 on [Ca²⁺]_B. Conclusions. Our study further supports the association of SNP rs1006737 with BD-I and suggests that CACNA1C SNP rs1006737 and Bcl-2 SNP rs956572, or specific causal variants in LD with these proxies, act independently to increase risk and ICDH in BD-I.     

Association study of CACNA1C polymorphisms with large artery atherosclerotic stroke in Chinese Han population

Aims Ischemic stroke (IS) is one of the most common diseases of neurology and the main cause of death and disability in Chinese population. CACNA1C was considered to be involved in the process of atherosclerosis, but there was little information about the association between genotypic polymorphisms of CACNA1C and ischemic stroke. Our study was designed to elucidate the relationship between four single-nucleotide polymorphisms (SNPs) variants in CACNA1C gene and the risk of large-artery atherosclerotic (LAA) stroke patients.

Methods A total of 384 subjects were enrolled in this study, including 192 LAA stroke cases and 192 healthy controls. And four SNPs variants in CNCNA1C gene were genotyped using in-house developed multiplex tagged-amplicon deep sequencing (TAm-Seq). Statistical analysis were conducted using χ2 test and binary logistic regression analysis.

Results We found one variant was significantly associated with LAA stroke in the allele models (rs10848683, p = 0.036, OR = 1.371, 95%CI: 1.021–1.841). And rs10848683 was also found to associate with LAA stroke under recessive model (p = 0.027, OR = 0.618, 95% CI: 0.403–0.947) after adjustment for gender and age. We also found that significant difference existed between haplotypes (rs229961-rs215976-rs216008-rs10848683) and LAA stroke (C-T-C-C, p = 0.017, OR = 2.265, 95%CI: 1.136–4.518; G-C-C-C, p = 0.046, OR = 1.891, 95% CI: 1.003–3.565; C-T-C-T, p = 0.001, OR = 0.256, 95%CI: 0.101–0.645).

Conclusion The results suggested that there was a potential association between CNCNA1C gene and the risk factor of LAA stroke in Chinese Han population.     

Is the CACNA1A gene involved in familial migraine with aura?

The discovery of mutations in the neural calcium channel (CACNA1A) gene in familial hemiplegic migraine (FHM), variant of migraine with aura, led to the suggestion that this gene might be involved in familial migraine with aura (FMA). We investigated whether the mutations in FHM are present in FMA patients, analyzing genomic DNA by PCR, single stranded conformation polymorphism, sequencing and restriction enzyme. No mutations were found. A known polymorphism (5682–14C>T) was found in exon 36. These findings suggest that the mutations found in FHM and the other known mutations of the CACNA1A gene are not the genetic basis of FMA. Genetic alterations in FMA patients may be localized on chromosome 19 but not in the CACNA1A exons we investigated. Received: 25 January 2002 / Accepted in revised form: 25 February 2002     

Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto‐hippocampal connectivity

Background: Genome‐wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto‐hippocampal connectivity. Methods: We used functional magnetic resonance imaging to measure neural activation during an n‐back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working‐memory‐related DLPFC activation and functional integration using a seed region functional connectivity approach. Results: Rs1006737 genotype was associated with altered right‐hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G‐allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto‐hippocampal connectivity with rs1006737 A alleles. Conclusions: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype‐related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder. Hum Brain Mapp 35:1190–1200, 2014. © 2013 Wiley Periodicals, Inc.     

BAD knockout provides metabolic seizure resistance in a genetic model of epilepsy with sudden unexplained death in epilepsy

Metabolic alteration, either through the ketogenic diet (KD) or by genetic alteration of the BAD protein, can produce seizure protection in acute chemoconvulsant models of epilepsy. To assess the seizure‐protective role of knocking out (KO) the Bad gene in a chronic epilepsy model, we used the Kcna1^?/? model of epilepsy, which displays progressively increased seizure severity and recapitulates the early death seen in sudden unexplained death in epilepsy (SUDEP). Beginning on postnatal day 24 (P24), we continuously video monitored Kcna1^?/? and Kcna1^?/? Bad^?/? double knockout mice to assess survival and seizure severity. We found that Kcna1^?/? Bad^?/? mice outlived Kcna1^?/? mice by approximately 2 weeks. Kcna1^?/? Bad^?/? mice also spent significantly less time in seizure than Kcna1^?/? mice on P24 and the day of death, showing that BadKO provides seizure resistance in a genetic model of chronic epilepsy.     

Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models

Cannabinoid receptor 1 (CB₁ receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB₁ expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB₁ signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB₁ downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi‐quantitative immunohistochemistry, we confirmed previous studies showing that CB₁ expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB₁ is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)‐expressing interneurons while remaining unchanged in parvalbumin‐ and calretinin‐expressing interneurons. CB₁ downregulation in striatal NPY/nNOS‐expressing interneurons occurs in R6/2 mice, Hdh^Q150/Q150 mice and the caudate nucleus of patients with HD. In R6/2 mice, CB₁ downregulation in NPY/nNOS‐expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro‐survival signaling molecule cAMP response element‐binding protein in NPY/nNOS‐expressing interneurons. Loss of CB₁ signaling in NPY/nNOS‐expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.     

CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity

Recently, multiple genome-wide association studies have identified a genetic polymorphism (CACNA1C rs1006737) that appears to confer susceptibility for BD. This article aims to summarize the existing literature regarding the impact of rs1006737 on functional and structural neuroimaging intermediate phenotypes. Twenty eight articles, representing 2486 healthy participants, 369 patients with BD and 104 healthy first-degree relatives of patients with BD, are incorporated. Multiple studies have demonstrated structural differences, functional differences associated with emotion-related and frontal-executive tasks, and/or differences in behavioral task performance in risk allele carriers (AA or AG). Results comparing participants with BD to health controls are generally less pronounced than within-group genetic comparisons. The review concludes with an integration of how cardiovascular comorbidity may be a relevant mediator of the observed findings, and proposes future directions toward optimized therapeutic use of calcium channel blockers in BD.     

Evidence for cis‐acting regulation of ANK3 and CACNA1C gene expression

Quinn EM, Hill M, Anney R, Gill M, Corvin AP, Morris DW. Evidence for cis‐acting regulation of ANK3 and CACNA1C gene expression.
Bipolar Disord 2010: 12: 440–445. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Genome‐wide association studies (GWAS) have identified Ankyrin‐G (ANK3) and the α‐1C subunit of the L‐type voltage‐gated calcium channel (CACNA1C) as susceptibility genes for bipolar disorder. Available biological information on these genes suggests a potential molecular mechanism involving ion channel dysfunction. The associated single nucleotide polymorphisms (SNPs) at ANK3 (rs10994336) and CACNA1C (rs1006737) are both intronic with no obvious impact on gene function. We investigated whether, instead of affecting protein function, these risk variants might impact on gene regulation affecting expression. Methods: We have done this by testing for allelic expression imbalance (AEI) to identify cis‐acting regulatory polymorphisms. Results: We identified evidence of cis‐acting variation at both loci in HapMap Caucasian Europeans from Utah (CEU) lymphoblastoid cell lines. There was considerable evidence of AEI at ANK3 with more than half of all heterozygous samples (21 out of 34) for marker SNP rs3750800 showing AEI and a small number of samples showing near monoallelic expression. The AEI at either gene could not be attributed to the GWAS‐associated SNPs. Conclusions: These data indicate that there is genetic variation local to both genes affecting their expression, but that this variation is not responsible for increasing risk of bipolar disorder.