Heterozygous Deletion of SCN2A and SCN3A in a Patient with Autism
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The Mineralocorticoid Receptor Leads to Increased Expression of EGFR
www.nature.com/scientificreports OPEN The mineralocorticoid receptor leads to increased expression of EGFR and T‑type calcium channels that support HL‑1 cell hypertrophy Katharina Stroedecke1,2, Sandra Meinel1,2, Fritz Markwardt1, Udo Kloeckner1, Nicole Straetz1, Katja Quarch1, Barbara Schreier1, Michael Kopf1, Michael Gekle1 & Claudia Grossmann1* The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important efector of the renin–angiotensin–aldosterone‑system and elicits pathophysiological efects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR‑mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identifed a SNP within the EGFR promoter that modulates MR‑induced EGFR expression. In RNA‑sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to diferential expression of cardiac ion channels, especially of the T‑type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone‑ and EGF‑responsiveness of CACNA1H expression was confrmed in HL‑1 cells by Western blot and by measuring peak current density of T‑type calcium channels. Aldosterone‑induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T‑type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL‑1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an efect on HL‑1 cell diameter, and the extent of this regulation seems to depend on the SNP‑216 (G/T) genotype. -
Chromosomal Aberrations in Head and Neck Squamous Cell Carcinomas in Norwegian and Sudanese Populations by Array Comparative Genomic Hybridization
825-843 12/9/08 15:31 Page 825 ONCOLOGY REPORTS 20: 825-843, 2008 825 Chromosomal aberrations in head and neck squamous cell carcinomas in Norwegian and Sudanese populations by array comparative genomic hybridization ERIC ROMAN1,2, LEONARDO A. MEZA-ZEPEDA3, STINE H. KRESSE3, OLA MYKLEBOST3,4, ENDRE N. VASSTRAND2 and SALAH O. IBRAHIM1,2 1Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Jonas Lies vei 91; 2Department of Oral Sciences - Periodontology, Faculty of Medicine and Dentistry, University of Bergen, Årstadveien 17, 5009 Bergen; 3Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, 0310 Oslo; 4Department of Molecular Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway Received January 30, 2008; Accepted April 29, 2008 DOI: 10.3892/or_00000080 Abstract. We used microarray-based comparative genomic logical parameters showed little correlation, suggesting an hybridization to explore genome-wide profiles of chromosomal occurrence of gains/losses regardless of ethnic differences and aberrations in 26 samples of head and neck cancers compared clinicopathological status between the patients from the two to their pair-wise normal controls. The samples were obtained countries. Our findings indicate the existence of common from Sudanese (n=11) and Norwegian (n=15) patients. The gene-specific amplifications/deletions in these tumors, findings were correlated with clinicopathological variables. regardless of the source of the samples or attributed We identified the amplification of 41 common chromosomal carcinogenic risk factors. regions (harboring 149 candidate genes) and the deletion of 22 (28 candidate genes). Predominant chromosomal alterations Introduction that were observed included high-level amplification at 1q21 (harboring the S100A gene family) and 11q22 (including Head and neck squamous cell carcinoma (HNSCC), including several MMP family members). -
Phenotypic Spectrum and Long-Term Outcome in Children with Genetic Causes of Early-Onset Epileptic Encephalopathy
Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy Chunhui Hu Department of Neurology, Children’s Hospital of Fudan University Deying Liu Wuhan Children’s hospital, Tongji Medical college, Huazhong University of Science & Technology Tian Luo Department of Neurology, Children’s Hospital of Fudan University Yi Wang ( [email protected] ) Department of Neurology, Children’s Hospital of Fudan University Zhisheng Liu Wuhan Children’s hospital, Tongji Medical college, Huazhong University of Science & Technology Research Article Keywords: Phenotypic spectrum, Long-term outcome, Genetic, EOEE, Therapy Posted Date: March 11th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-257334/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/23 Abstract Background To explore the clinical phenotype and long-term outcome in children with genetic causes of early-onset epileptic encephalopathies. Methods The clinical data of 118 children between 2010 and 2020 was obtained and analyzed. The whole exome sequencing and copy number variation studies in family were used to nd pathogenic mutations. The conrmed mutations were veried by Sanger sequencing. Results Among 118 patients, 39 patients were diagnosed with DS, 18 were WS, 3 were OS, 3 were EME, 2 were MMFSI, 1 was GLUT1 deciency syndrome, 1 was Pyridoxine dependent epilepsy and 51 were non-symptomatic EOEEs. The initial EEG showed frequent multiple and multifocal sharp waves, spike waves, sharp slow waves or spike slow waves. In the later period, some transformed into infrequent discharging or normal EEG. 112 patients (112/118, 94.9%) showed normal brain MRI, and the remaining 6 had widened extracerebral space. -
An Advance About the Genetic Causes of Epilepsy
E3S Web of Conferences 271, 03068 (2021) https://doi.org/10.1051/e3sconf/202127103068 ICEPE 2021 An advance about the genetic causes of epilepsy Yu Sun1, a, *, †, Licheng Lu2, b, *, †, Lanxin Li3, c, *, †, Jingbo Wang4, d, *, † 1The School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801-3633, US 2High School Affiliated to Shanghai Jiao Tong University, Shanghai, 200441, China 3Applied Biology program, University of British Columbia, Vancouver, V6r3b1, Canada 4School of Chemical Machinery and Safety, Dalian University of Technology, Dalian, 116023, China †These authors contributed equally. Abstract: Human hereditary epilepsy has been found related to ion channel mutations in voltage-gated channels (Na+, K+, Ca2+, Cl-), ligand gated channels (GABA receptors), and G-protein coupled receptors, such as Mass1. In addition, some transmembrane proteins or receptor genes, including PRRT2 and nAChR, and glucose transporter genes, such as GLUT1 and SLC2A1, are also about the onset of epilepsy. The discovery of these genetic defects has contributed greatly to our understanding of the pathology of epilepsy. This review focuses on introducing and summarizing epilepsy-associated genes and related findings in recent decades, pointing out related mutant genes that need to be further studied in the future. 1 Introduction Epilepsy is a neurological disorder characterized by 2 Malfunction of Ion channel epileptic seizures caused by abnormal brain activity. 1 in Functional variation in voltage or ligand-gated ion 100 (50 million people) people are affected by symptoms channel mutations is a major cause of idiopathic epilepsy, of this disorder worldwide, with men, young children, and especially in rare genetic forms. -
Spatial Distribution of Leading Pacemaker Sites in the Normal, Intact Rat Sinoa
Supplementary Material Supplementary Figure 1: Spatial distribution of leading pacemaker sites in the normal, intact rat sinoatrial 5 nodes (SAN) plotted along a normalized y-axis between the superior vena cava (SVC) and inferior vena 6 cava (IVC) and a scaled x-axis in millimeters (n = 8). Colors correspond to treatment condition (black: 7 baseline, blue: 100 µM Acetylcholine (ACh), red: 500 nM Isoproterenol (ISO)). 1 Supplementary Figure 2: Spatial distribution of leading pacemaker sites before and after surgical 3 separation of the rat SAN (n = 5). Top: Intact SAN preparations with leading pacemaker sites plotted during 4 baseline conditions. Bottom: Surgically cut SAN preparations with leading pacemaker sites plotted during 5 baseline conditions (black) and exposure to pharmacological stimulation (blue: 100 µM ACh, red: 500 nM 6 ISO). 2 a &DUGLDFIoQChDQQHOV .FQM FOXVWHU &DFQDG &DFQDK *MD &DFQJ .FQLS .FQG .FQK .FQM &DFQDF &DFQE .FQM í $WSD .FQD .FQM í .FQN &DVT 5\U .FQM &DFQJ &DFQDG ,WSU 6FQD &DFQDG .FQQ &DFQDJ &DFQDG .FQD .FQT 6FQD 3OQ 6FQD +FQ *MD ,WSU 6FQE +FQ *MG .FQN .FQQ .FQN .FQD .FQE .FQQ +FQ &DFQDD &DFQE &DOP .FQM .FQD .FQN .FQG .FQN &DOP 6FQD .FQD 6FQE 6FQD 6FQD ,WSU +FQ 6FQD 5\U 6FQD 6FQE 6FQD .FQQ .FQH 6FQD &DFQE 6FQE .FQM FOXVWHU V6$1 L6$1 5$ /$ 3 b &DUGLDFReFHSWRUV $GUDF FOXVWHU $GUDD &DY &KUQE &KUP &KJD 0\O 3GHG &KUQD $GUE $GUDG &KUQE 5JV í 9LS $GUDE 7SP í 5JV 7QQF 3GHE 0\K $GUE *QDL $QN $GUDD $QN $QN &KUP $GUDE $NDS $WSE 5DPS &KUP 0\O &KUQD 6UF &KUQH $GUE &KUQD FOXVWHU V6$1 L6$1 5$ /$ 4 c 1HXURQDOPURWHLQV -
Identifying Genes in Monoamine Nuclei That May Determine Stress Vulnerability and Depressive Behavior in Wistar–Kyoto Rats
Neuropsychopharmacology (2006) 31, 2449–2461 & 2006 Nature Publishing Group All rights reserved 0893-133X/06 $30.00 www.neuropsychopharmacology.org Identifying Genes in Monoamine Nuclei that may Determine Stress Vulnerability and Depressive Behavior in Wistar–Kyoto Rats 1 2 2 ,1 Kimberly A Pearson , Alisson Stephen , Sheryl G Beck and Rita J Valentino* 1Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 2Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA The Wistar–Kyoto (WKY) rat is stress sensitive and exhibits depressive-like behavior. The locus coeruleus (LC)–norepinephrine and dorsal raphe (DR)–serotonin systems mediate certain aspects of the stress response and have been implicated in depression. Microarray technology was used to identify gene expression differences in the LC and DR between WKY vs Sprague–Dawley (SD) rats that might account for the WKY phenotype. RNA was isolated from microdissected LC and DR, amplified, and hybridized to microarrays (1 array/ subject, n ¼ 4/group). Significance of microarray (SAM) analysis revealed increased expression of 66 genes in the LC and 19 genes in the DR and decreased expression of 33 genes in the DR of WKY rats. Hierarchical clustering identified differences in gene expression profiles of WKY vs SD rats that generally concurred with SAM. Notably, genes that encoded for enzymes involved in norepinephrine turnover, amino-acid receptors, and certain G-protein-coupled receptors were elevated in the LC of WKY rats. The DR of WKY rats showed decreased expression of genes encoding several potassium channels and neurofilament genes. The chromosomal locations of 15 genes that were differentially expressed in WKY rats were near loci identified as contributing to depressive-like behaviors in the rat. -
Unveiling Genomic Regions That Underlie Differences Between Afec-Assaf Sheep and Its Parental Awassi Breed
Seroussi et al. Genet Sel Evol (2017) 49:19 DOI 10.1186/s12711-017-0296-3 Genetics Selection Evolution RESEARCH Open Access Unveiling genomic regions that underlie differences between Afec‑Assaf sheep and its parental Awassi breed Eyal Seroussi, Alexander Rosov, Andrey Shirak, Alon Lam and Elisha Gootwine* Abstract Background: Sheep production in Israel has improved by crossing the fat-tailed local Awassi breed with the East Friesian and later, with the Booroola Merino breed, which led to the formation of the highly prolific Afec-Assaf strain. This strain differs from its parental Awassi breed in morphological traits such as tail and horn size, coat pigmentation and wool characteristics, as well as in production, reproductive and health traits. To identify major genes associated with the formation of the Afec-Assaf strain, we genotyped 41 Awassi and 141 Afec-Assaf sheep using the Illumina Ovine SNP50 BeadChip array, and analyzed the results with PLINK and EMMAX software. The detected variable genomic regions that differed between Awassi and Afec-Assaf sheep (variable genomic regions; VGR) were compared to selection signatures that were reported in 48 published genome-wide association studies in sheep. Because the Afec-Assaf strain, but not the Awassi breed, carries the Booroola mutation, association analysis of BMPR1B used as the test gene was performed to evaluate the ability of this study to identify a VGR that includes such a major gene. Results: Of the 20 detected VGR, 12 were novel to this study. A ~7-Mb VGR was identified on Ovies aries chromo- some OAR6 where the Booroola mutation is located. -
The Genes Pme-1 and Pme-2 Encode Two Poly(ADP-Ribose) Polymerases in Caenorhabditis Elegans Steve N
Biochem. J. (2002) 368, 263–271 (Printed in Great Britain) 263 The genes pme-1 and pme-2 encode two poly(ADP-ribose) polymerases in Caenorhabditis elegans Steve N. GAGNON*, Michael O. HENGARTNER† and Serge DESNOYERS*1 *Department of Pediatrics, Laval University Medical Research Centre and Faculty of Medicine, Laval University, Quebec, Canada, and †Institute of Molecular Biology, University of Zu$ rich, Winterthurerstrasse 190, 8057 Zu$ rich, Switzerland Poly(ADP-ribose) polymerases (PARPs) are an expanding, well- domain of PARPs in general and shares 24% identity with conserved family of enzymes found in many metazoan species, huPARP-2. Recombinant PME-1 and PME-2 display PARP including plants. The enzyme catalyses poly(ADP-ribosyl)ation, activity, which may partially account for the similar activity a post-translational modification that is important in DNA found in the worm. A partial duplication of the pme-1 gene with repair and programmed cell death. In the present study, we pseudogene-like features was found in the nematode genome. report the finding of an endogenous source of poly(ADP- Messenger RNA for pme-1 are 5h-tagged with splice leader 1, ribosyl)ation in total extracts of the nematode Caenorhabditis whereas those for pme-2 are tagged with splice leader 2, suggesting elegans. Two cDNAs encoding highly similar proteins to human an operon-like expression for pme-2. The expression pattern of PARP-1 (huPARP-1) and huPARP-2 are described, and we pme-1 and pme-2 is also developmentally regulated. Together, propose to name the corresponding enzymes poly(ADP-ribose) these results show that PARP-1 and -2 are conserved in evolution metabolism enzyme 1 (PME-1) and PME-2 respectively. -
Sodium Channel Mutations in Epilepsy and Other Neurological Disorders
Sodium channel mutations in epilepsy and other neurological disorders Miriam H. Meisler, Jennifer A. Kearney J Clin Invest. 2005;115(8):2010-2017. https://doi.org/10.1172/JCI25466. Review Series Since the first mutations of the neuronal sodium channelS CN1A were identified 5 years ago, more than 150 mutations have been described in patients with epilepsy. Many are sporadic mutations and cause loss of function, which demonstrates haploinsufficiency of SCN1A. Mutations resulting in persistent sodium current are also common. Coding variants of SCN2A, SCN8A, and SCN9A have also been identified in patients with seizures, ataxia, and sensitivity to pain, respectively. The rapid pace of discoveries suggests that sodium channel mutations are significant factors in the etiology of neurological disease and may contribute to psychiatric disorders as well. Find the latest version: https://jci.me/25466/pdf Review series Sodium channel mutations in epilepsy and other neurological disorders Miriam H. Meisler and Jennifer A. Kearney Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. Since the first mutations of the neuronal sodium channel SCN1A were identified 5 years ago, more than 150 muta- tions have been described in patients with epilepsy. Many are sporadic mutations and cause loss of function, which demonstrates haploinsufficiency of SCN1A. Mutations resulting in persistent sodium current are also common. Coding variants of SCN2A, SCN8A, and SCN9A have also been identified in patients with seizures, ataxia, and sen- sitivity to pain, respectively. The rapid pace of discoveries suggests that sodium channel mutations are significant factors in the etiology of neurological disease and may contribute to psychiatric disorders as well. -
Oestrogen Receptor Β Mediates the Actions of Bisphenol-A on Ion Channel Expression in Mouse Pancreatic Beta Cells
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by idUS. Depósito de Investigación Universidad de Sevilla Diabetologia (2019) 62:1667–1680 https://doi.org/10.1007/s00125-019-4925-y ARTICLE Oestrogen receptor β mediates the actions of bisphenol-A on ion channel expression in mouse pancreatic beta cells Juan Martinez-Pinna1,2,3 & Laura Marroqui1,2,4 & Abdelkrim Hmadcha4,5 & Javier Lopez-Beas4,5 & Sergi Soriano1,2,3 & Sabrina Villar-Pazos1,2,4 & Paloma Alonso-Magdalena1,2,4 & Reinaldo S. Dos Santos1,2,4 & Ivan Quesada1,2,4 & Franz Martin4,5 & Bernat Soria4,5 & Jan-Åke Gustafsson6,7 & Angel Nadal1,2,4 Received: 18 February 2019 /Accepted: 26 April 2019 /Published online: 27 June 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Aims/hypothesis Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical that has been associated with type 2 dia- betes development. Low doses of BPA modify pancreatic beta cell function and induce insulin resistance; some of these effects are mediated via activation of oestrogen receptors α (ERα)andβ (ERβ). Here we investigated whether low doses of BPA regulate the expression and function of ion channel subunits involved in beta cell function. Methods Microarray gene profiling of isolated islets from vehicle- and BPA-treated (100 μg/kg per day for 4 days) mice was performed using Affymetrix GeneChip Mouse Genome 430.2 Array. Expression level analysis was performed using the nor- malisation method based on the processing algorithm ‘robust multi-array average’. Whole islets or dispersed islets from C57BL/ 6J or oestrogen receptor β (ERβ) knockout (Erβ−/−) mice were treated with vehicle or BPA (1 nmol/l) for 48 h. -
Original Article ITGA8 Accelerates Migration and Invasion of Myeloma Cells in Multiple Myelomas
Int J Clin Exp Med 2021;14(2):1126-1132 www.ijcem.com /ISSN:1940-5901/IJCEM0122176 Original Article ITGA8 accelerates migration and invasion of myeloma cells in multiple myelomas Mengmeng Cui1, Jiangfang Feng1, Xuezhong Gu2, Zhuowei Zhang3, Junxia Zhao1, Hongmei Chai1, Jing Li4, Zheng Xu5 1Department of Hematology, Jincheng General Hospital, Jincheng, Shanxi Province, China; 2Department of He- matology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China; 3Personnel Depart- ment of Shanxi Medical University, Taiyuan, Shanxi Province, China; 4Department of Oncology, Jincheng General Hospital, Jincheng, Shanxi Province, China; 5Department of Orthopaedics, Jincheng General Hospital, Jincheng, Shanxi Province, China Received September 11, 2020; Accepted October 14, 2020; Epub February 15, 2021; Published February 28, 2021 Abstract: Multiple myeloma is cancer of the plasma cells and is the second most common cancer of the blood system, which is characterized by increased calcium levels, renal insufficiency, anemia, bone disease, and suscep- tibility to infection due to suppression of immunoglobulin production. Early diagnosis of multiple myeloma is difficult as it has no symptoms until it reaches an advanced stage. Therefore, key genes involved in the pathogenesis of multiple myeloma might be significant markers for early diagnosis and treatment of the disease. We analyzed the differentially expressed genes in patients with multiple myeloma using sequencing microarrays from the GEO da- tabase. Combined with GO and KEGG analysis, we identified ITGA8 as a key target in the pathogenesis of multiple myeloma, and further verified the differential expression of ITGA8 in myeloma cell lines by rtPCR experiments. Our study contributes to a better understanding of the development of multiple myeloma and advances the application of bioinformatics in clinical diagnosis. -
Genetic Variations Associated with Pharmacoresistant Epilepsy (Review)
MOLECULAR MEDICINE REPORTS 21: 1685-1701, 2020 Genetic variations associated with pharmacoresistant epilepsy (Review) NOEMÍ CÁRDENAS-RODRÍGUEZ1*, LILIANA CARMONA-APARICIO1*, DIANA L. PÉREZ-LOZANO1,2, DANIEL ORTEGA-CUELLAR3, SAÚL GÓMEZ-MANZO4 and IVÁN IGNACIO-MEJÍA5,6 1Laboratory of Neuroscience, National Institute of Pediatrics, Ministry of Health, Coyoacán, Mexico City 04530; 2Department of Postgraduate of Medical, Dental and Health Sciences, Clinical Experimental Health Research, National Autonomous University of Mexico, Mexico City 04510; Laboratories of 3Experimental Nutrition and 4Genetic Biochemistry, National Institute of Pediatrics, Ministry of Health, Coyoacán, Mexico City 04530; 5Laboratory of Translational Medicine, Military School of Health Graduates, Lomas de Sotelo, Militar, Mexico City 11200; 6Section of Research and Graduate Studies, Superior School of Medicine, National Polytechnic Institute, Mexico City 11340, Mexico Received August 28, 2019; Accepted January 16, 2020 DOI: 10.3892/mmr.2020.10999 Abstract. Epilepsy is a common, serious neurological disorder the pathophysiological processes that underlie this common worldwide. Although this disease can be successfully treated human neurological disease. in most cases, not all patients respond favorably to medical treatments, which can lead to pharmacoresistant epilepsy. Drug-resistant epilepsy can be caused by a number of mecha- Contents nisms that may involve environmental and genetic factors, as well as disease- and drug-related factors. In recent years, 1. Introduction numerous studies have demonstrated that genetic variation is 2. Pharmacoresistant epilepsy involved in the drug resistance of epilepsy, especially genetic 3. Genetic variations associated with pharmacoresistant variations found in drug resistance-related genes, including epilepsy the voltage-dependent sodium and potassium channels genes, 4. The role of genetic variants in the diagnosis and treatment and the metabolizer of endogenous and xenobiotic substances of pharmacoresistant epilepsy genes.