EGAGenomicsProfessor Erichttps://ega-archive.org/dacs/EGAC00001000621EGAEGA DAC EGAC00001000621EGAeric.schulze-bahr@ukmuenster.de<h4>Rationale</h4>Familial sinus node and atrioventricular conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue, and syncope because of a temporarily or permanently reduced heart rate. To date, only a few genes for familial sinus and atrioventricular conduction dysfunction are known, and the majority of cases remain pathogenically unresolved.<h4>Objective</h4>We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB.<h4>Methods and results</h4>Genome-wide linkage analysis mapped the SND+AVB disease locus to chromosome 7q21.1-q31.1 (2-point logarithm of the odds score: 4.64; θ=0); in this region, targeted exome sequencing identified a novel heterozygous mutation (p.Arg52Leu) in the <i>GNB2</i> gene that strictly cosegregated with the SND+AVB phenotype. <i>GNB2</i> encodes the β₂ subunit (Gβ₂) of the heterotrimeric G-protein complex that is being released from G-protein-coupled receptors on vagal stimulation. In 2 heterologous expression systems (HEK-293T cells and <i>Xenopus laevis</i> oocytes), an enhanced activation of the G-protein-activated K⁺ channel (GIRK; Kir3.1/Kir3.4) was shown when mutant Gβ₂ was coexpressed with Gγ₂; this was in contrast to coexpression of mutant Gβ₂-Gγ₂ with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ₂ to cardiac GIRK channels when compared with native Gβ₂.<h4>Conclusions</h4>A <i>GNB2</i> gene mutation is associated with familial SND+AVB and leads to a sustained activation of cardiac GIRK channels, which is likely to hyperpolarize the myocellular membrane potential and thus reduces their spontaneous activity. Our findings describe for the first time a role of a mutant G-protein in the nonsyndromic pacemaker disease because of GIRK channel activation.A Mutation in the G-Protein Gene <i>GNB2</i> Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction.Stallmeyer Birgit B, Kuß Johanna J, Kotthoff Stefan S, Zumhagen Sven S, Vowinkel Kirsty K, Rinné Susanne S, Matschke Lina A LA, Friedrich Corinna C, Schulze-Bahr Ellen E, Rust Stephan S, Seebohm Guiscard G, Decher Niels N, Schulze-Bahr Eric EWES, Complete Transcriptome, Exome Sequencing, Whole Exome, Complete, Complete Transcriptome Sequencing, Exome Sequencings, Client., Complete Exome Sequencings, Patient, Complete Exome, Clients, Whole, Complete Exome Sequencing, Whole Transcriptome Sequencing, Whole Exome Sequencing, Exome, Whole Transcriptome, Transcriptome Sequencing, Transcriptome Sequencings, SequencingSino-Atrial, dysfunction., Materials, Node, protein complex, Sino-Atrial Nodes, sinu-atrial node, Proteins, familial, SA node, Sinu-Atrial Node, Gene, Sinoatrial Nodes, Sinus, Sinu-Atrial Nodes, protein, Sinu-Atrial, protein-containing complex, Cistrons, Mutations, cardiac pacemaker, sinus node of Keith and Flack, native protein, Sinuatrial, Sinus Node, Protein, Gene Products, Genetic Materials, protein aggregate, Gnb-2, Genetic Material, Sino Atrial Node, Sinu Atrial Node, sinuatrial nodal muscle tissue, Genetic, sinus node, INSDC_feature:gene, nodus sinuatrialis, pathophysiology, Sinoatrial, Sinus Nodes, node of Keith-Flack, Protein Gene Products, genetic, Gene Proteins, SA nodal muscle tissue, sinoatrial node, Material, Sino-Atrial Node, Nodes, Cistron, inherited genetic, sinuatrial node, Sinuatrial Nodes, constitutitional genetic, hereditary, Sinuatrial Node, Koch's nodeHeart, Eph-like tyrosine kinase 1, Situational Syncopes, Materials, Kinship, Sino-Atrial Nodes, acetylglucosaminyltransferase-like protein, PNT-P1, FON1, Vertigo, Carotid Sinus Syncopes, Syncopal Vertigo, EY3-1, Deglutitional Syncopes, FLORAL ORGAN NUMBER 1, Syncopal Episodes, Long Term, Mutations, sinus node of Keith and Flack, Method, 1802), Orthostasis, symptoms, Life Cycle, Whole Transcriptome, Transcriptome Sequencing, AV, D-ets-2, 3520, myd, Human embryo kinase, TYRO4, Hyperventilation, RCB2202, HEK293T, Kinship Network, like-acetylglucosaminyltransferase, Genomes, EK4, Bdr, Mbp-1, Tiredness, procedures, SNAP-25, Delta Psi, geographical area, Xenopus laevis (Daudin, atrioventricular bundle, Cardiogenic Syncope, ion channels, Role Concepts, Homo sapiens disease, Conduction Block, sinuatrial node, Chronotropism, CXXC finger protein 9, CACH2, screening, Atrioventricular Conduction Block, Dizzyness, Effort Syncopes, Difference, Resting Potential, sinu-atrial node, Exome, familial, Longterm Effect, clawed frog <Xenopus laevis>, Convulsive Syncope, Procedure, cardiac pacemaker, Role Concept, BCNG-2, Sinus Node, mKIAA0609, Role, GENA70, trls, SSS2, activation, fg, Cchl1a1, Complete Transcriptome, Deglutitional Syncope, pntP2, Pointed-P1, Cardiac Chronotropism, CaV1.2, Ets94F, signs, INSDC_feature:gene, Methodological, whole genome, Weariness, Phenotypes, MDC1D, Situational Syncope, enr, Chromosome, Material, Whole Exome Sequencing, Sinuatrial Node, Platannas, FLORAL DEFECTIVE 10, Sino-Atrial, 0998/12, Heart Rate Control, nasal sinus, region or site annotation, Potential, Effects, Tired, Heartbeats, SUPERMAN, Sinu-Atrial, protein-containing complex, LARGE1, Cav1.2, pulse rate, Aim, AIM, DMPOINT1A, Rate, Cardiac, Micturition Syncope, Gene Products, disease or disorder, clawed frog, Technique, Postural, gamma-subunit, DNMT1, positional, Complete, Exome Sequencings, pointed-RC, Transmembrane Electrical Potential Difference, DNMT1_HUMAN, Ion Channel, Longterm, MDDGB6, Tussive Syncope, ligand, dysfunction, MBC, sinus node, Syncope, AV block, cardiac chronotropy, Long-Term, Sinus Nodes, node of Keith-Flack, EK3-2, Sequencing, A-V bundle, Study, API6, l(3)07825, AV Blocks, Convulsive, fasciculus atrioventricularis, Whole Exome, HEK-293T, Presyncopes, Whole, CG17077, His bundle, constitutitional genetic, Koch's node, ETK, Convulsive Syncopes, DNA (cytosine-5)-methyltransferase 1, Ets, atrioventricular bundle muscle tissue, findings, Complete Exome Sequencings, Family Research, X. laevis, Proteins, disorders, Sinu-Atrial Node, Atrioventricular, Sinus, Synaptosomal-associated 25 kDa protein, MCMT, HAC-1, Cell, Stokes-Adams, Concept, Family Members, prophase chromosome, Exome Sequencing, native protein, Fatigue, chemical analysis, Long Term Effects, condition, Bufo laevis, Xenopus leavis, pnt-P1, pnt-P2, CXXC9, Postural Syncope, Vertigos, CT-2, underdeveloped, Tussive, interphase chromosome, nodus sinuatrialis, CACNL1A1, CXXC-type zinc finger protein 9, primary structure of sequence macromolecule, Longterm Effects, Gene Proteins, Transmembrane Potential Difference, like-glycosyltransferase, Families, Resting Membrane Potential, platanna, Membrane Potentials, Cardiac Rates, X. laevi, hereditary, Relatives, Platanna, General activity, CLEC2C, POINT, CG8705, Networks, Cardiogenic, Node, Lightheadedness, Activity, HSN1E, determination, Conduction Blocks, Membrane Potential, DmelCG17077, Fainting, Mbp1, ETK1, Ovocytes, Stokes-Adams Syncope, Pnt, protein, Ovocyte, Techniques, png, diseases, Roles, Ionic Channels, Light Headedness, SUP, Cardiogenic Syncopes, Concepts, diseases and disorders, Transmembrane Potential Differences, protein aggregate, Effect, Sino Atrial Node, Pulse Rates, Family Life Cycle, Pnt-P1, Sinu Atrial Node, human disease, Differences, Complete Exome Sequencing, Whole Transcriptome Sequencing, hypoplasia, beta-subunit, chromatid, Sinoatrial, Super protein, sp, Carotid Sinus, genetic, atrioventricular block (disease), Hek 293T, Methodological Studies, Ionic Channel, Transmembrane Potentials, atrioventricular block, Family Life Cycles, BCNG2, Long-Term Effects, activation., Oocyte, TS, Effort, wide/broad, LQT8, gyltl1b-b, African clawed frog, MELC-CC, Sinoatrial Nodes, D-Ets-2, ets94F, common platanna, 0123/09, results, Postural Syncopes, MDDGA6, AVB, atrio-ventricular bundle, CCHL1A1, Atrioventricular Blocks, Diseases, Carotid Sinus Syncope, EPH-like kinase 4, Genetic Materials, Tussive Syncopes, AV nodal block, KIAA0609, Filiation, Genetic Material, acetylglucosaminyltransferase-like 1A, Light-Headedness, ADCADN, Potential Differences, gyltl1b, positional polypeptide feature, artificial pacemaker, UNQ203/PRO229, Syncopal Episode, DNA (cytosine-5-)-methyltransferase 1, Channels, Effort Syncope, mdc1d, Situational, Control, hEK4, Membrane Channels, LARGE_HUMAN, Methodological Study, 293 T, lightheadedness, Heart Rate, ptd, Life Cycles, disease, PntP2, wide, bundle of His, atrioventricular fasciculus, Resting Potentials, PntP1, E(E2F)3D, Nodes, HEK, Episode, Cistron, inherited genetic, PNTP2, Resting Membrane Potentials, Sinuatrial Nodes, Tyrosine-protein kinase receptor ETK1, Fainting spell, Transcriptome Sequencings, PNTP1, heterotrimeric G-protein GTPase activity, other disease, Transmembrane, Family Member, Procedures, 293tsA1609neo, Complete Exome, ETS2, Ets2, heterotrimeric G-protein GTPase, SA node, Gene, Drop Attacks, Network, broad, Potential Difference, froggy, Gyltl1a, 293T, Presyncope, rate of heart contraction, pntegfr, dizzy, HAC1, 0608/07, HEK4, Syncopal, reduced, Chronotropy, Drop, Cardiac Chronotropy, Studies, tiny, AV Block, Ionic, Gnb-2, Tyrosine-protein kinase TYRO4, WES, Hyperventilation Syncope, Hyperventilation Syncopes, Genetic, 293-T, Research, Transmembrane Potential, LARGE, Lassitude, non-neoplastic, BPFD#36, Blocks, Mif1, AV bundle, 2.7.10.1, SA nodal muscle tissue, Atrioventricular Conduction Blocks, Deglutitional, disorder, Long-Term Effect, Membrane Channel, Kinship Networks, Drop Attack, Family, l(3)j1B7, DNA MTase HsaI, small, Stokes Adams, Human Embryonic Kidney 293T, protein complex, DNMT, Micturition, HEK 293 T, Sinu-Atrial Nodes, medical condition, Cistrons, Syncopes, Channel, Sinuatrial, Micturition Syncopes, DNA methyltransferase HsaI, Protein, Pulse Rate, sequence, rare (European definition), techniques, Heartbeat, Block, l(3)s118306, pacemaker, sinuatrial nodal muscle tissue, Stokes-Adams Syncopes, Complete Transcriptome Sequencing, CACN2, Resting, Dizziness, FLO10, pathophysiology, Membrane, HERP, Protein Gene Products, Cardiac Rate, Ets58AB, Heart Rates, Pulse, sinoatrial node, Ion, Sino-Atrial Node, Attack, SNAP, Potentials, assay, Rate Control, D930026N18Rik, alpha-subunit, HEK-293-T, m.HsaI, glycosyltransferase-like protein LARGE1, methodologyfalseWhole exome sequencing in cardiovascular patientsData Access Committee EGAC00001000621

2025-1-9

EGAC00001000621960628219978EGAS00001002319EGAD00001003328