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Ibrahim El-Battrawy, Zhihan Zhao, Huan Lan, Xin Li, Gökhan Yücel, Siegfried Lang, Katherine Sattler, Jan-Dierk Schünemann, Wolfram-Hubertus Zimmermann, Lukas Cyganek, Jochen Utikal, Thomas Wieland, Karen Bieback, Ralf Bauer, Antonius Ratte, Regina Pribe-Wolferts, Kleopatra Rapti, Daniel Nowak, Janina Wittig, Dierk Thomas, Patrick Most, Hugo A Katus, Ursula Ravens, Constanze Schmidt, Martin Borggrefe, Xiao-Bo Zhou, Oliver J Müller, Ibrahim Akin
BACKGROUND: Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis...
March 2018: Circ Genom Precis Med
Germano Orrù, Mauro Giovanni Carta
Background: Bipolar Disorder (BD), along with depression and schizophrenia, is one of the most serious mental illnesses, and one of the top 20 causes of severe impairment in everyday life. Recent molecular studies, using both traditional approaches and new procedures such as Whole-Genome Sequencing (WGS), have suggested that genetic factors could significantly contribute to the development of BD, with heritability estimates of up to 85%. However, it is assumed that BD is a multigenic and multifactorial illness with environmental factors that strongly contribute to disease development/progression, which means that progress in genetic knowledge of BD might be difficult to interpret in clinical practice...
2018: Clinical Practice and Epidemiology in Mental Health: CP & EMH
Hao Yu, Hao Yan, Lifang Wang, Jun Li, Liwen Tan, Wei Deng, Qi Chen, Guigang Yang, Fuquan Zhang, Tianlan Lu, Jianli Yang, Keqing Li, Luxian Lv, Qingrong Tan, Hongyan Zhang, Xiao Xiao, Ming Li, Xin Ma, Fude Yang, Lingjiang Li, Chuanyue Wang, Tao Li, Dai Zhang, Weihua Yue
BACKGROUND: Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatment response is highly variable. Little is known about the genetic factors associated with treatment response. We did a genome-wide association study of antipsychotic treatment response in patients with schizophrenia. METHODS: The discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China that are part of the Chinese Antipsychotics Pharmacogenomics Consortium...
March 1, 2018: Lancet Psychiatry
Kimberley J Billingsley, Maurizio Manca, Olympia Gianfrancesco, David A Collier, Helen Sharp, Vivien J Bubb, John P Quinn
Genomic wide association studies identified the CACNA1C locus as genetically associated with both schizophrenia and bipolar affective disorder. CACNA1C encodes Cav1.2, one of four subunits of L-type voltage gated calcium channels. Variation resides in non-coding regions of CACNA1C which interact with the promoter and are validated expression quantitative trait loci. Using reporter gene constructs we demonstrate the CACNA1C promoter is a major mediator of inducible regulation of CACNA1C activity in the SH-SY5Y neuroblastoma cell line...
February 28, 2018: Schizophrenia Research
Thassio R Mesquita, Gaelle Auguste, Debora Falcón, Gema Ruiz-Hurtado, Rogelio Salazar-Enciso, Jessica Sabourin, Florence Lefebvre, Say Viengchareun, Hussein Kobeissy, Patrick Lechêne, Valerie Nicolas, Amaya Fernández-Celis, Susana Gomez, Sandra Lauton-Santos, Eric Morel, Angelica Rueda, Natalia López-Andrés, Ana M Gomez, Marc Lombes, Jean-Pierre Benitah
<u>Rationale:</u> The mineralocorticoid receptor (MR) antagonists belong to the current therapeutic armamentarium for the management of cardiovascular diseases, but the mechanisms conferring their beneficial effects are poorly understood. Part of the cardiovascular effects of MR are due to the regulation of L-type Cav 1.2 Ca2+ channel expression, which is generated by tissue-specific alternative promoters as a long 'cardiac' (Cav 1.2-LNT) or a short 'vascular' (Cav 1.2-SNT) N-terminal transcripts...
February 21, 2018: Circulation Research
Hiroshi Komoda, Aya Shiraki, Jun-Ichi Oyama, Toshiyuki Nishikido, Koichi Node
AIM: Recently, calcium channel blockers (CCBs) have been reported to reduce atherosclerosis with anti-inflammatory or antiatherosclerotic effects in vivo. It is well established that monocytes and macrophages play important roles in promoting atherosclerosis. However, the effects of CCBs on macrophage activation remain unclear. The aim of this study was to evaluate the effects of azelnidipine, a dihydropyridine L-type CCB, on the activation of macrophages and to clarify the mechanisms of the effects of CCBs on atherosclerosis...
February 3, 2018: Journal of Atherosclerosis and Thrombosis
Advithi Rangaraju, Shuba Krishnan, G Aparna, Satish Sankaran, Ashraf U Mannan, B Hygriv Rao
Electrical storm (ES) is a life threatening clinical situation. Though a few clinical pointers exist, the occurrence of ES in a patient with remote myocardial infarction (MI) is generally unpredictable. Genetic markers for this entity have not been studied. In the present study, we carried out genetic screening in patients with remote myocardial infarction presenting with ES by next generation sequencing and identified 25 rare variants in 19 genes predominantly in RYR2, SCN5A, KCNJ11, KCNE1 and KCNH2, CACNA1B, CACNA1C, CACNA1D and desmosomal genes - DSP and DSG2 that could potentially be implicated in electrical storm...
January 30, 2018: Indian Pacing and Electrophysiology Journal
Johannes T Krautheim, Benjamin Straube, Udo Dannlowski, Martin Pyka, Henriette Schneider-Hassloff, Rebecca Drexler, Axel Krug, Jens Sommer, Marcella Rietschel, Stephanie H Witt, Tilo Kircher
A high frequency of outgroup contact - as experienced by urban dwellers and migrants - possibly increases schizophrenia risk. This risk might be further amplified by genetic and environmental risk factors, such as the A-allele of rs1006737 within the Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C) gene and Childhood Interpersonal Trauma (CIT). Both have been related to ventral anterior cingulate cortex (vACC) functioning. We investigated vACC functioning, during ingroup and outgroup emotion perception in relation to rs1006737 and CIT...
January 29, 2018: Social Cognitive and Affective Neuroscience
Ellen Ngar Yun Poon, Baixia Hao, Daogang Guan, Mulin Jun Li, Jun Lu, Yong Yang, Binbin Wu, Stanley Chun Ming Wu, Sarah E Webb, Yan Liang, Andrew L Miller, Xiaoqiang Yao, Junwen Wang, Bin Yan, Kenneth R Boheler
Aims: MicroRNAs (miRNAs) are crucial for the post-transcriptional control of protein-encoding genes, and together with transcription factors (TFs) regulate gene expression; however, the regulatory activities of miRNAs during cardiac development are only partially understood. In this study, we tested the hypothesis that integrative computational approaches could identify miRNAs that experimentally could be shown to regulate cardiomyogenesis. Methods and results: We integrated expression profiles with bioinformatics analyses of miRNA and TF regulatory programs to identify candidate miRNAs involved with cardiac development...
January 24, 2018: Cardiovascular Research
Izabela M Krzyzewska, Judith B M Ensink, Laura Nawijn, Adri N Mul, Saskia B Koch, Andrea Venema, Vinod Shankar, Jessie L Frijling, Dirk J Veltman, Ramon J L Lindauer, Miranda Olff, Marcel M A M Mannens, Mirjam van Zuiden, Peter Henneman
Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that may develop after a traumatic event. Here we aimed to identify epigenetic and genetic loci associated with PTSD. We included 73 traumatized police officers with extreme phenotypes regarding symptom severity despite similar trauma history: n = 34 had PTSD and n = 39 had minimal PTSD symptoms. Epigenetic and genetic profiles were based on the Illumina HumanMethylation450 BeadChip. We searched for differentially methylated probes (DMPs) and differentially methylated regions (DMRs)...
January 23, 2018: European Journal of Human Genetics: EJHG
Xiaoyan Yang, Xiaofang Mao, Gao Xu, Shasha Xing, Ansuman Chattopadhyay, Si Jin, Guy Salama
BACKGROUND: In long QT type-2 (LQT2), women are more prone to lethal arrhythmias called Torsade de Pointes (TdP) than men. We previously reported that 17-β-estradiol (E2) upregulates L-type Ca2+-channels and current (ICa,L) (∼30%) in rabbit ventricular myocytes by a classical genomic-mechanism mediated by estrogen-receptor-α (ER)α. In LQT2 ( IKr-blockade or bradycardia), the higher Ca2+ influx via ICa,L, causes Ca2+-overload, spontaneous sarcoplasmic reticulum Ca2+-release, and re-activation of ICa,L that trigger early afterdepolarizations (EADs) and TdP...
January 9, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Ai Kojima, Fumiaki Shikata, Toru Okamura, Takashi Higaki, Seiko Ohno, Minoru Horie, Shunji Uchita, Yujiro Kawanishi, Kenji Namiguchi, Takumi Yasugi, Hironori Izutani
BACKGROUND: Congenital long QT syndrome (LQTS) can cause ventricular arrhythmic events with syncope and sudden death resulting from malignant torsades de pointes (TdP) followed by ventricular fibrillations (VFs). However, the syndrome is often overlooked prior to the development of arrhythmic events in patients with congenital heart diseases demonstrating right bundle branch block on electrocardiogram (ECG). We present a case of an adult patient with congenital heart disease who developed VFs postoperatively, potentially due to his mutation in a LQTS related gene, which was not identified on preoperative assessment due to incomplete evaluation of his family history...
December 19, 2017: Journal of Cardiothoracic Surgery
Soo Hyun Seo, So Yeon Kim, Sung Im Cho, Hyunwoong Park, Seungjun Lee, Jong Moon Choi, Man Jin Kim, Jee Soo Lee, Kyung Jin Ahn, Mi Kyoung Song, Eun Jung Bae, Sung Sup Park, Moon Woo Seong
Long QT syndrome (LQTS) is an inherited cardiac disease characterized by a prolonged heart rate-corrected QT (QTc) interval. We investigated the genetic causes in patients with prolonged QTc intervals who were negative for pathogenic variants in three major LQTS-related genes (KCNQ1, KCNH2, and SCN5A). Molecular genetic testing was performed using a panel including 13 LQTS-related genes and 67 additional genes implicated in other cardiac diseases. Overall, putative genetic causes of prolonged QTc interval were identified in three of the 30 patients (10%)...
January 2018: Annals of Laboratory Medicine
Jieyun Bai, Kuanquan Wang, Yashu Liu, Yacong Li, Cuiping Liang, Gongning Luo, Suyu Dong, Yongfeng Yuan, Henggui Zhang
Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF). This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF. The Ten Tusscher-Panfilov (TP06) human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D) fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR) curves, dispersion of repolarization (DOR), QT interval and spiral wave dynamics...
2017: Frontiers in Physiology
Ambrin Fatima, Muhammad Farooq, Uzma Abdullah, Muhammad Tariq, Tanveer Mustafa, Muhammad Iqbal, Niels Tommerup, Shahid Mahmood Baig
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...
September 2017: Psychiatry Investigation
Jaakko T Leinonen, Lia Crotti, Aurora Djupsjöbacka, Silvia Castelletti, Nella Junna, Alice Ghidoni, Annukka M Tuiskula, Carla Spazzolini, Federica Dagradi, Matti Viitasalo, Kimmo Kontula, Maria-Christina Kotta, Elisabeth Widén, Heikki Swan, Peter J Schwartz
BACKGROUND: Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. METHODS AND RESULTS: The study included 76 Finnish and Italian patients with a mean age of 31...
October 5, 2017: International Journal of Cardiology
Chiara Fabbri, Filippo Corponi, Diego Albani, Ilaria Raimondi, Gianluigi Forloni, Koen Schruers, Siegfried Kasper, Alexander Kautzky, Joseph Zohar, Daniel Souery, Stuart Montgomery, Carlotta Pia Cristalli, Vilma Mantovani, Julien Mendlewicz, Alessandro Serretti
A candidate gene and a genome-wide approach were combined to study the pharmacogenetics of antidepressant response and resistance. Investigated genes were selected on the basis of pleiotropic effect across psychiatric phenotypes in previous genome-wide association studies and involvement in antidepressant response. Three samples with major depressive disorder (total=671) were genotyped for 44 SNPs in 8 candidate genes (CACNA1C, CACNB2, ANK3, GRM7, TCF4, ITIH3, SYNE1, FKBP5). Phenotypes were response/remission after 4weeks of treatment and treatment-resistant depression (TRD)...
February 2, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
Kendra K S Nordgren, Marshall Hampton, Kendall B Wallace
Doxorubicin (DOX) is a widely used treatment for human cancers, but increases the risk of life-threatening congestive heart failure (CHF). DOX-induced mitochondrial damage is cumulative and persistent, similar to that observed clinically for risk of CHF. Recent evidence suggests the persistent nature of this injury is caused by altered regulation of genes important to normal cardiac functioning. We hypothesize that chronic DOX therapy is associated with epigenetic modifications of DNA methylation status, particularly in critical regulators of mitochondrial function and capacity...
October 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Juejin Wang, Guang Li, Dejie Yu, Yuk Peng Wong, Tan Fong Yong, Mui Cheng Liang, Ping Liao, Roger Foo, Uta C Hoppe, Tuck Wah Soong
Recently, we reported that homozygous deletion of alternative exon 33 of CaV1.2 calcium channel in the mouse resulted in ventricular arrhythmias arising from increased CaV1.2Δ33 ICaL current density in the cardiomyocytes. We wondered whether heterozygous deletion of exon 33 might produce cardiac phenotype in a dose-dependent manner, and whether the expression levels of RNA splicing factors known to regulate alternative splicing of exon 33 might change in human heart failure. Unexpectedly, we found that exon 33(+/-) cardiomyocytes showed similar CaV1...
September 26, 2017: Channels
Daniel G Ehlinger, Kathryn G Commons
Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of-function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1...
October 2017: European Journal of Neuroscience
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