CACNA1C Research Articles

Comparison of Galaxy and Unix tools for analyzing the exome sequencing data from syndactyly abnormalities

Syndactyly is a congenital limb abnormality, which manifests as the fusion of digits due to incomplete separation during embryonic development, and its pathogenesis involves intricate genetic and molecular processes. Since Exome sequencing has gained widespread utilization as an invaluable tool for exploring genetic disorders during prenatal development, the Bioinformatic platforms, such as GALAXY and UNIX, play a central role in the analysis process of exome sequencing data, facilitating precise identification and interpretation of genetic variations linked to congenital abnormalities. In this study, we conducted a comparative analysis of exome sequencing data from a 1.5-year-old syndactyly patient using two platforms: GALAXY and UNIX. The UNIX platform identified a total of 275,572 variants, and the GALAXY platform identified 140,291 variants when compared with the Grch38/hg38 reference genome. A comparative analysis identified 126,848 common variants between the platforms. After filtration with the 200 syndactyly-related genes, 1,345 variants were remained. The distribution of these 1,345 variants spans the entirety of the patient's genome, with focal concentrations observed on specific chromosomes including chromosomes 2, 4, and 11. Concurrently, within the top 200 genes implicated in syndactyly, the genes FRAS1, CACNA1C, GLI2, and NOTCH1 exhibit the highest frequency of variants. These data emphasized the impact of the chosen analytical platform on genetic variation detection in congenital limb abnormalities, provided critical insights into the selection of bioinformatic tools for optimizing exome sequencing workflows in the context of limb malformations, contributed to advancements in genetic research and diagnostic methodologies.

The genetic association between bipolar disorder and dementia: a qualitative review.

Bipolar disorder is a chronic disorder characterized by fluctuations in mood state and energy and recurrent episodes of mania/hypomania and depression. Bipolar disorder may be regarded as a neuro-progressive disorder in which repeated mood episodes may lead to cognitive decline and dementia development. In the current review, we employed genome-wide association studies to comprehensively investigate the genetic variants associated with bipolar disorder and dementia. Thirty-nine published manuscripts were identified: 20 on bipolar disorder and 19 on dementia. The results showed that the genes CACNA1C, GABBR2, SCN2A, CTSH, MSRA, and SH3PXD2A were overlapping between patients with bipolar disorder and dementia. In conclusion, the genes CACNA1C, GABBR2, SCN2A, CTSH, MSRA, and SH3PXD2A may be associated with the neuro-progression of bipolar disorder to dementia. Further genetic studies are needed to comprehensively clarify the role of genes in cognitive decline and the development of dementia in patients with bipolar disorder.

Voltage-gated ion channel’s gene expression in the myocardium of embryo and adult chickens

The functioning of the cardiovascular system is critical for embryo survival. Cardiac contractions depend on the sequential activation of different classes of voltage-gated ion channels. Understanding the fundamental features of these interactions is important for identifying the mechanisms of pathologies development in the myocardium. However, at present there is no consensus on which ion channels are involved in the formation of automaticity in the early embryonic stages. The aim of this study was to elucidate the expression of genes encoding various types of ion channels that are involved in the generation of electrical activity chicken heart at different stages of ontogenesis. We analyzed the expression of 14 genes from different families of ion channels. It was revealed that the expression profiles of ion channel genes change depending on the stages of ontogenesis. The HCN4, CACNA1D, SCN1A, SCN5A, KCNA1 genes have maximum expression at the tubular heart stage. In adult, a switch occurs to the higher expression of CACNA1C, KCNH6, RYR and SLC8A1 genes. This data correlated with the results obtained by the microelectrode method. It can be assumed that the automaticity of the tubular heart is mainly due to the mechanism of the «membrane–clock» (hyperpolarization-activated current (If), Ca2+–current L–type (ICaL), Na+–current (INa) and the slow component of the delayed rectifier K+–current (IKs)). Whereas in adult birds, the mechanism for generating electrical impulses is determined by both « membrane– clock» and «Ca2+–clock».

Prenatal methamphetamine hydrochloride exposure downregulates miRNA-151-3p and CACNA1C in testis rats' offspring.

Due to the widespread use of methamphetamine (METH) among reproductive-aged women, the effects of intrauterine exposure to METH need to be investigated, as previous studies on this topic have been limited. The goal of this study is to examine the influence of two regulatory genes (miRNA-151-3p and CACNA1C) on the intrauterine life of mice exposed to METH. Pregnant mice received doses of 2 and 5 mg/kg of METH and saline from day 10 of pregnancy until the end. Their offspring were then evaluated for miRNA-151-3p and CACNA1C gene expression levels using real-time PCR. The findings indicated that exposure to METH reduced the expression levels of both miRNA-151-3p and CACNA1C genes in offspring compared to the control group (p≤0.001). In conclusion, intrauterine exposure to METH leads to a decrease in expression levels of both miRNA-151-3p and CACNA1C genes, potentially disrupting regulatory pathways involving these genes and having an impact on male reproductive health.

Generating a human induced pluripotent stem cell line (XACHi018-A) from a Timothy syndrome infant carrying heterozygous CACNA1C c.1216G>A (p.G406R) mutation

Timothy syndrome, an extremely rare disease, is closely associated with a mutation in CACNA1C gene, which encodes the cardiac L-type voltage-gated calcium channel (Cav1.2). In this study, we generated a human induced pluripotent stem cell (iPSC) line from a Timothy syndrome infant carrying heterozygous CACNA1C mutation (transcript variant NM_000719.7c.1216G>A: p.G406R). The generated iPSC line showed typical stem cell morphology, positively expressed pluripotency and proliferation markers, normal karyotype, and trilineage differentiation potential. Therefore, this patient-specific iPSC can be of great significance in investigating the mechanisms underlying Timothy syndrome, and hence establishing effective intervention strategies.

In vivo calcium and voltage mapping of the zebrafish heart

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (FWO) Purpose Inherited cardiac arrhythmias are characterized by a disturbance in the normal electrical functioning of the heart due to a dysfunction of cardiac ion channels, accessory proteins and/or structural components. This complex process is difficult to model in vitro, while in vivo mouse models differ substantially from humans with regards to cardiac electrophysiology. Thus, there is a need for alternative disease models in cardiac arrhythmia research. The zebrafish heart shows remarkable similarity to humans in its electrocardiogram and action potential (AP) morphology. Due to the optical translucency of zebrafish larvae, it is possible visualize the cardiac calcium and voltage dynamics across their entire hearts in vivo by use of genetically encoded calcium and voltage indicators (GECI and GEVI). We combined the fast kinetics of a next generation voltage reporter (Ace2N-mNeon) with a spectrally compatible calcium sensor (R-GECO) to create a sensitive high throughput method for in vivo characterization of the cardiac AP. Methods Ace2N-mNeon and R-GECO were expressed under control of a myocardial specific promoter via the Tol2kit system. The effect of sensor expression on normal physiology was assessed by patch clamp experiments. Fluorescence recordings were obtained with a Leica SP8 DLS microscope and a custom-built light sheet microscope. Our zebrafish sensor line was validated by experiments with quinidine drug exposure, as well as a novel model for long QT syndrome (LQTS) with a knock-in (KI) mutation in the cacna1c gene. Results Sensor expression did not significantly alter cardiac electrophysiology. The tg(myl7:Ace2N-mNeon/R-GECO) line demonstrated alterations in the heart rate, depolarization and repolarization induced by quinidine exposure. We observed a significantly prolonged ventricular repolarization in the LQTS KI line. Three-dimensional optical maps of AP characteristics across the entire zebrafish heart exhibited the physiological characteristics of the zebrafish cardiac electrophysiology, with activation initiated at the atrial venous pole and propagated towards the ventricular outflow tract, prolonged repolarization in the ventricles compared to the atria and slowed depolarization in the atrio-ventricular canal. Conclusion By expressing Ace2N-mNeon and R-GECO in the zebrafish heart, we were able to accurately detect drug- and mutation induced alterations in the cardiac AP, as well as AP characteristics across the entire heart, without compromising normal cardiac electrophysiology. Our transgenic line will provide a promising assay for future studies of cardiac arrhythmia.

Current real-world evidence of genetic testing diagnostic yield in a large cohort of long QT syndrome

Abstract Background Diagnostic yield in long QT syndrome (LQTS) ranges between 30-70%, depending on the studied population. LQTS can lead to an unexpected sudden cardiac death. For this reason and due to its wider current availability, genetic testing in patients with suspicion of LQTS has spread. Purpose The aim of this study is to investigate the genetic testing yield among a large cohort of heterogeneous index cases with LQTS phenotype. Methods Diagnostic yield was restrospectively evaluated in a cohort of index cases referred to our laboratory for genetic study with LQTS phenotype. Genetic study was performed with customized libraries through next generation sequencing (NGS), which included copy number variations (CNVs) analysis. Patients with LQTS phenotype studied both with "long QT panels" and with broader cardiovascular panels were included, but those with additional cardiac phenotype (cardiomyopathies, heart defects or catecholaminergic polymorphic ventricular tachycardia) were excluded. Positive genetic reports were considered when a likely pathogenic (LP) or pathogenic (P) variant could explain patient´s phenotype. Inconclusive reports were described when a variant considered risk factor (RF) or a variant of uncertain significance variant (VUS) or a hot-VUS was identified in a clinically relevant gene. Results 1183 index cases were genotyped for LQTS phenotype. Only 164 index cases (13,8%) were studied with broader panels which included between 77 and 368 genes. The rest (n=1019) were studied with LQTS panels (either with small panels which included KCNQ1, KCNH2, KCNE1, KCNE2, SCN5A, KCNJ2, CACNA1C and with up to 36 genes-QT panels). Around 27% (n=321) of the index cases had a positive result. They carried LP/P variants in the following genes: KCNQ1 (n=166, 52%), KCNH2 (n=112), SCN5A (n=25), RYR2 (n=5), CACNA1C (n=3), HCN4 (n=4), KCNJ2 (n=2), KCNE2 (n=2) and CALM2 (n=1). 53,3% of the reports were negative. However, there were some incidental findings: 2 index cases carried P variants in LDLR, 2 carried P variants in PKP2, 2 carried a P variant in MYBPC3 and 1 index case each carried a P variant in DES, TTN and DSG2. From the 231 inconclusive reports, 37 index cases carried the RF variant in KCNE1 (p.Asp85Asn), 2 carried the RF variant in SCN5A (p.Arg1193Gln) and 50 patients carried hot-VUS in KCNQ1, KCNH2, CACNA1C, SCN5a or RYR2 gene. Conclusions In our large cohort of index cases referred for genetic testing for LQTS, diagnostic yield was around 27% when considering only LP/P variants in LQTS or arrhythmic phenotype related genes. Even by including the inconclusive but potentially relevant genetic results (RF and hot VUS), the diagnostic yield in our cohort reaches 35%. This is lower than expected for LQTS cohort. It should be taken into consideration that our cohort consists of heterogeneous patients referred for LQTS genetic testing, which would probably reflects better the real world patients seen in every day practice.

Amygdala-specific changes in Cacna1c, Nfat5, and Bdnf expression are associated with stress responsivity in mice: A possible mechanism for psychiatric disorders

The CACNA1C gene encodes the alpha-1c subunit of the Cav1.2 calcium channel, a regulator of neuronal calcium influx involved in neurotransmitter release and synaptic plasticity. Genetic data show a role for CACNA1C in depressive symptoms underlying different psychiatric diagnoses. However, the mechanisms involved still require further exploration. This study aimed to investigate sex and region-specific changes in the Cacna1c gene and behavioral outcomes in mice exposed to chronic stress. Moreover, we evaluated the Nuclear factor of activated T-cells 5 (Nfat5) and the Brain-derived neurotrophic factor (Bdnf) as potential upstream and downstream Cacna1c targets and their correlation in stressed mice and humans with depression. Male and female Swiss mice were exposed to chronic unpredictable stress (CUS) for 21 days. Animal-integrated emotionality was assessed using the sucrose splash test, the tail suspension, the open-field test, and the elevated-plus-maze. Gene expression analysis was performed in the amygdala, prefrontal cortex, and hippocampus. Human data for in silico analysis was obtained from the Gene Expression Omnibus. CUS-induced impairment in integrated emotional regulation was observed in males. Gene expression analysis showed decreased levels of Cacna1c and Nfat5 and increased levels of Bdnf transcripts in the amygdala of stressed male mice. In contrast, there were no major changes in behavioral responses or gene expression in female mice after stress. The expression of the three genes was significantly correlated in the amygdala of mice and humans. The strong and positive correlation between Canac1c and Nfat5 suggests a potential role for this transcription factor in Canac1c expression. These changes could impact amygdala reactivity and emotional responses, making them a potential target for psychiatric intervention.

A Novel Variant of CACNA1C Subtype Related Disorders: A Neonate with Dysmorphism and Distal Skeletal Defects

The mutation of CACNA1C gene on chromosome 12p13, has known to be associated with disorder with hypotonia, language delay, and skeletal defects with or without seizures (NEDHLSS). We report neonate with a novel variant of CACNA1C subtype related disorder with dysmorphisms and distal skeletal dysplasia.

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation.

Background: CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. Methods and Results: We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. Conclusions: The present study highlights the importance of considering the investigation of the CACNA1C gene in children's neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.

Effects of CACNA1C and ANK3 on cognitive function in patients with bipolar disorder

Bipolar disorder (BD) is a complex, severe mental illness with cognitive impairment. Impairments in attention and memory are particularly evident. A large number of previous studies have identified CACNA1C and ANK3 gene variants as risk factors for BD and both affect cognitive function in people with BD. However, it is unclear whether there is an interaction effects between the two genes on cognitive impairment in patients. We used 153 Chinese Han Chinese patients with BD to explore the association of CACNA1C and ANK3 variants with attention and immediate memory using Plink software and and performed a epistatic interaction effects analysis. We found that CACNA1C and ANK3 gene variants respectively affected patients' scores on attention and memory tests. The significant SNP in the CACNA1C and ANK3 genes are rs73042126(P = 3.16 × 10−5,FDR = 0.0253) and rs2393640(P = 1.50 × 10−4,FDR = 0.0353) respectively. And they also interacted to affect cognitive functioning in BD patients (attention: P = 0.0289; immediate memory: P = 0.0398). Follow-up studies should increase the sample size, improve the assessment methods and experimental design, and further explore the pathogenic mechanisms of BD.

Transmural APD heterogeneity determines ventricular arrhythmogenesis in LQT8 syndrome: Insights from Bidomain computational modeling.

Long QT Syndrome type 8 (LQT8) is a cardiac arrhythmic disorder associated with Timothy Syndrome, stemming from mutations in the CACNA1C gene, particularly the G406R mutation. While prior studies hint at CACNA1C mutations' role in ventricular arrhythmia genesis, the mechanisms, especially in G406R presence, are not fully understood. This computational study explores how the G406R mutation, causing increased transmural dispersion of repolarization, induces and sustains reentrant ventricular arrhythmias. Using three-dimensional numerical simulations on an idealized left-ventricular model, integrating the Bidomain equations with the ten Tusscher-Panfilov ionic model, we observe that G406R mutation with 11% and 50% heterozygosis significantly increases transmural dispersion of repolarization. During S1-S4 stimulation protocols, these gradients facilitate conduction blocks, triggering reentrant ventricular tachycardia. Sustained reentry pathways occur only with G406R mutation at 50% heterozygosis, while neglecting transmural heterogeneities of action potential duration prevents stable reentry, regardless of G406R mutation presence.

Protective effect of human epicardial adipose-derived stem cells on myocardial injury driven by poly-lactic acid nanopillar array.

We investigated if poly-lactic acid (PLA) nanopillar array can trigger the differentiation of human epicardial (ADSCs) (heADSCs) into cardiomyocyte-like cells and explored the effects of these cardiomyocyte-like cells on myocardial infarction (MI) in vivo. PLA nanopillar array (200nm diameter) and plain PLA film (PLA planar) induced heADSCs were marked with carboxyfluorescein. After 7 days, the expressions of myocardiocyte-specific genes were significantly enhanced in cells seeded on PLA nanopillar array compared with that on PLA planar, especially CACNA1C, KCNH2, and MYL2 genes (p<0.05). However, the expressions of cardiac troponin T (cTNT), KCNQ1, and KCNA5 were lower than those in PLA planar-induced heADSCs (p<0.05), whereas GATA4 tended to increase with time. The cells with positively stained α-actinin and cTNT were elevated in heADSCs induced by PLA nanopillar array compared with those induced by PLA planar only (p<0.05). In vivo experiments showed that cardiac function was improved after injecting PLA-nanopillar array-induced heADSCs into the ischemic heart (p<0.05, compared with PLA planar+MI group). Furthermore, tyrosine hydroxylase density was significantly lower (p<0.05). PLA nanopillar array directly drives the differentiation of heADSCs into cardiomyocyte-like cells, and the induced heADSCs exhibit a protective effect on ischemic myocardium by improving cardiac function in MI rats.

The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.

Wildtype peers rescue social play and 50-kHz ultrasonic vocalization deficits in juvenile female Cacna1c heterozygous rats.

Healthy brain development depends on early social practices and experiences. The risk gene CACNA1C is implicated in numerous neuropsychiatric disorders, in which key characteristics include deficits in social functioning and communication. Recently, we reported sex-dependent impairments in social behavior and ultrasonic vocalizations (USV) in juvenile heterozygous Cacna1c+/- (HET) rats. Specifically, HET females displayed increases in rough-and-tumble play that eliminated the typically observed sex difference between male and female rats. Interestingly, female wild-type Cacna1c+/+ (WT) pairs also showed a similar increase in social play when housed with HET females, suggesting their behavior may be influenced by HET cage mates. This indicates that the genetic makeup of the social environment related to Cacna1c can influence social play, yet systematic studies are lacking. In the present study, we housed juvenile females in MIXED- or SAME-genotype cages and tested them in a social play paradigm with a same- and opposite-genotype partner. The results show that the early social environment and the genotype of the play partner influence social play and 50-kHz USV emission. Experience with a WT play partner appears necessary for HET females to show comparable levels of play and 50-kHz USV emission. Same-genotype HET pairs played less and emitted fewer 50-kHz USV than same-genotype WT or opposite-genotype pairs; however, we found that the decrease in social play and 50-kHz USV in HET pairs can be rescued by playing with a WT partner. The effect was particularly prominent when the first play partner was WT, as we found it increased play and 50-kHz USV emission in all subsequent interactions with ensuing partners. These findings suggest that the genetic makeup related to the social environment and/or social peers influences social play in Cacna1c+/- haploinsufficient rats. Specifically, our results show that WT peers can rescue behavior and communication alterations in Cacna1c female rats. Our findings have important implications because they show that the genetic makeup of the social environment can divulge phenotypic changes in genetic rat models of neuropsychiatric disorders.

Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders.

Neuropsychiatric disorders are highly heritable and have overlapping genetic underpinnings. Single nucleotide polymorphisms (SNPs) in the gene CACNA1C have been associated with several neuropsychiatric disorders, across multiple genome-wide association studies. A total of 70,711 subjects from 37 independent cohorts with 13 different neuropsychiatric disorders were meta-analyzed to identify overlap of disorder-associated SNPs within CACNA1C. The differential expression of CACNA1C mRNA in five independent postmortem brain cohorts was examined. Finally, the associations of disease-sharing risk alleles with total intracranial volume (ICV), gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA), and average cortical thickness (TH) were tested. Eighteen SNPs within CACNA1C were nominally associated with more than one neuropsychiatric disorder (P < .05); the associations shared among schizophrenia, bipolar disorder, and alcohol use disorder survived false discovery rate correction (five SNPs with P < 7.3 × 10-4 and q < 0.05). CACNA1C mRNA was differentially expressed in brains from individuals with schizophrenia, bipolar disorder, and Parkinson's disease, relative to controls (three SNPs with P < .01). Risk alleles shared by schizophrenia, bipolar disorder, substance dependence, and Parkinson's disease were significantly associated with ICV, GMVs, SA, or TH (one SNP with P ≤ 7.1 × 10-3 and q < 0.05). Integrating multiple levels of analyses, we identified CACNA1C variants associated with multiple psychiatric disorders, and schizophrenia and bipolar disorder were most strongly implicated. CACNA1C variants may contribute to shared risk and pathophysiology in these conditions.

Enantioselective effect of trifloxystrobin in early-stage zebrafish (Danio rerio) embryos: Cardiac abnormalities impacted by E,E-trifloxystrobin enantiomer

Trifloxystrobin (TFS) is one of the extensively used strobilurin fungicides, which is composed of four enantiomers and its active form is E,E-TFS. In this study, we assess the acute toxicity of four enantiomers, E,E−, E,Z-, Z,E−, and Z,Z-TFS in zebrafish (Danio rerio) embryos. Among the four enantiomers, only E,E-TFS was found to be acutely toxic, with an estimated LC50 value of 0.68 mg/L. Treatment with E,E-TFS resulted in various phenotypic changes in the embryos, including pericardial and yolk-sac edema, spine curvature, and blood pooling. And it shortened the whole body length in the treated embryos by increasing the total intersegmental vessel numbers using a Tg(fli1a:EGFP) zebrafish line. Further study using Tg(cmlc2:EGFP) zebrafish line revealed that E,E-TFS treatment was associated with cardiac malformations, a failure of heart function, and a lowered heartbeat rate at the concentration of 0.25 mg/L. Also, the differential gene expression analysis identified significant down-regulation of vmhc and cacna1c genes encoding ventricular myosin heavy chain and calcium voltage-gated channel subunit alpha 1C, which are crucial for heart development. These results suggest the need for regular monitoring of E,E-TFS enantiomers after field application and further research into their potential chronic effects on environmental organisms.

Electrical, structural, and autonomic atrial remodeling underlies atrial fibrillation in inflammatory atrial cardiomyopathy.

There is growing evidence indicating a close relationship between inflammation and atrial fibrillation (AF). Although underlying inflammatory atrial cardiomyopathy may contribute to the development of AF, the arrhythmogenic remodeling caused by atrial inflammation has not been elucidated in detail. Herein, we examined electrical, structural, and autonomic changes in the atria in a mouse model of autoimmune myocarditis. BALB/c mice were immunized with cardiac myosin peptide (MyHC-α614-629) conjugated with complete Freund's adjuvant on days 0 and 7. Susceptibility to AF was assessed using right-atrial burst pacing. The mice immunized with MyHC-α614-629 showed an inflammatory atrial cardiomyopathy phenotype, with enlarged atria; a high degree of inflammatory cell infiltration primarily consisting of CD4+ T cells, CD8+ T cells, Ly6GlowCD11b+ macrophages, and CD11c+ dendritic cells; and severe interstitial fibrosis with collagen deposition. These mice demonstrated significantly enhanced susceptibility to AF, as indicated by their increased AF induction rate and duration. In addition, the expression of potassium channels (Kcnh2, Kcnd3, and Kcnj2) and calcium handling-associated genes (Cacna1c, Camk2, Ryr2, and Atp2a2) was downregulated. Connexin 40 expression was significantly downregulated, leading to frequent lateralization to the inflamed atrium. Sympathetic and parasympathetic innervation and neurotrophin expression (nerve growth factor and brain-derived neurotrophic factor) were upregulated in the inflamed atria. Inflammatory atrial cardiomyopathy promotes susceptibility to AF via arrhythmogenic electrical, structural, and autonomic remodeling of the atria.

Usefulness of salivary sampling for the molecular detection of a genetic variant associated with bipolar disorders.

Under certain conditions, the hyperthymic temperament traits associated with an increased risk of developing bipolar disorders may in fact produce adaptive responses. The purpose of this study is to see if the type of biological material used for genetic analysis (saliva or blood) affects the detection of mutations in the CACNA1C (RS1006737) gene. The first experimental group consisted of Sardinian migrants ("volunteers") in South American and European megacities. The second experimental group consisted of older healthy subjects with hyperactivity and novelty-seeking characteristics from Cagliari, Italy. The genetic procedure included DNA extraction, real-time PCR, and the Sanger method. Nonetheless, the authors believe that saliva is the most appropriate biological material, given its many advantages. In contrast to blood, saliva can be collected by any type of healthcare provider after following a few simple instructions.

Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics.

Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene CACNA1C encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of CACNA1C gene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation-transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.