EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD000010033281EGA dataset EGAD00001003328EGA<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 EVasp, VASP, Data Set., DmelCG15112, ENHANCER OF ATNSI ACTIVITY, MENA, NDPP1, l(2)02029, Enb, enb, ENA, Ena, CG15112, ENA/VASPpulmonary cone, WES, Complete Transcriptome, right ventricle pulmonary outflow tract, Complete, Materials, Complete Transcriptome Sequencing, Exome Sequencings, Genetic, Complete Exome Sequencings, Complete Exome Sequencing, RVOT, right ventricular outflow tract, Whole Transcriptome Sequencing, Exome, familial, Gene, arterial cone, infundibulum, conus arteriosus (infundibulum), conus arteriosus, INSDC_feature:gene, outflow tract of right ventricle, Cistrons, AI848635, Sequencing, genetic, Mutations, Exome Sequencing, pulmonary conus, Whole Exome, Material, Whole, Whole Exome Sequencing, infundibulum of right ventricle, Genetic Materials, TREK-1, A430027H14Rik, Cistron, inherited genetic, Whole Transcriptome, Transcriptome Sequencing, constitutitional genetic, hereditary, Transcriptome Sequencings, Genetic Material, Complete Exome.Sino-Atrial, dysfunction., Materials, Node, protein complex, Sino-Atrial Nodes, sinu-atrial node, Proteins, familial, AVCOND, SA node, Sinu-Atrial Node, Gene, Sinoatrial Nodes, Sinus, Sinu-Atrial Nodes, protein, Sinu-Atrial, Atrioventricular Conduction ECG Assessment, Atrioventricular Conduction, 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, KATP1, Mutations, sinus node of Keith and Flack, Sinus Node Dysfunction, Compared, EVS Concept Property, DmelCG12298, Method, 1802), Dynamics Simulation, Likely, Orthostasis, HEART, symptoms, Life Cycle, Related, SCRAMBLED, Whole Transcriptome, Transcriptome Sequencing, AV, Activate, D-ets-2, 3520, myd, Human embryo kinase, TYRO4, Hyperventilation, RCB2202, cardiac, Sequence Alteration, HEK293T, Gene Alteration, heterozygous genotype, Kinship Network, like-acetylglucosaminyltransferase, Gene Variation, Genomes, Subunit, Molecular, EK4, Bdr, Mbp-1, Comparison, Tiredness, procedures, SNAP-25, Delta Psi, Be, geographical area, Xenopus laevis (Daudin, atrioventricular bundle, Cardiogenic Syncope, Familiar, ion channels, Role Concepts, LOINC Axis 2, Homo sapiens disease, Conduction Block, Subfamily J, DNA Alteration, Relationship, sinuatrial node, Chronotropism, CXXC finger protein 9, Inwardly Rectifying Subfamily J, CACH2, screening, Atrioventricular Conduction Block, Dizzyness, Effort Syncopes, Difference, Resting Potential, sinu-atrial node, Exome, familial, STRUBBELIG, Longterm Effect, clawed frog <Xenopus laevis>, Convulsive Syncope, Procedure, cardiac pacemaker, Role Concept, Channel Object, BCNG-2, Sinus Node, mKIAA0609, CIR, Role, 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pointed-RC, Transmembrane Electrical Potential Difference, DNMT1_HUMAN, Activation, Ion Channel, Longterm, Rare Disorder, MDDGB6, Tussive Syncope, mei-1794, ligand, dysfunction, MBC, sinus node, Target, Syncope, AV block, cardiac chronotropy, Long-Term, Sinus Nodes, Coupling, node of Keith-Flack, EK3-2, Sequencing, Property, A-V bundle, Study, API6, l(3)07825, AV Blocks, Convulsive, fasciculus atrioventricularis, Whole Exome, HEK-293T, Presyncopes, Whole, CG17077, Expression, His bundle, constitutitional genetic, Koch's node, ETK, Convulsive Syncopes, DNA (cytosine-5)-methyltransferase 1, New, Probably, LQT13, Ets, atrioventricular bundle muscle tissue, Potassium Channel, Spontaneous, findings, Complete Exome Sequencings, Family Research, Released File, Acquisition Scheme, Heterozygous, X. laevis, Proteins, disorders, Sinu-Atrial Node, Atrioventricular, Protein Subunit, Sinus, Synaptosomal-associated 25 kDa protein, MCMT, HAC-1, Cell, Stokes-Adams, Concept, Family Members, prophase chromosome, Exome Sequencing, native protein, Fatigue, Long Term Effects, condition, Bufo laevis, Xenopus leavis, activate, pnt-P1, pnt-P2, CXXC9, Autosomal dominant type, Destination, Definitely Related to Intervention, Dynamic, Postural Syncope, Vertigos, CT-2, underdeveloped, Tussive, interphase chromosome, Cardiac ATP-Sensitive Potassium Channel Gene, Dub, Likeliness, Dynamics, nodus sinuatrialis, CACNL1A1, CXXC-type zinc finger protein 9, Locus, primary structure of sequence macromolecule, Longterm Effects, Gene Proteins, Transmembrane Potential Difference, like-glycosyltransferase, Families, Resting Membrane Potential, platanna, Membrane Potentials, Cardiac Rates, Gene Mutation, X. laevi, hereditary, Relatives, Platanna, General activity, CLEC2C, POINT, CG8705, Networks, Cardiogenic, Node, Lightheadedness, Activity, HSN1E, Conduction Blocks, Membrane Potential, objective, DmelCG17077, NCI Thesaurus Property, Fainting, Activated, Mbp1, ETK1, Ovocytes, Stokes-Adams Syncope, Pnt, protein, Atrioventricular Conduction, Ovocyte, released, Molecular Dynamic, SUB, KIR3.4, Techniques, png, diseases, Roles, Releasing, Ionic Channels, Light Headedness, SUP, Cardiogenic Syncopes, Concepts, diseases and disorders, Transmembrane Potential Differences, protein aggregate, Member 5 Gene, Effect, KIF20A, Sino Atrial Node, Pulse Rates, Family Life Cycle, Definite, gene expression, Pnt-P1, Sinu Atrial Node, Molecular Dynamics, Targeting, human disease, Identification, Differences, Complete Exome Sequencing, Whole Transcriptome Sequencing, hypoplasia, beta-subunit, Association, chromatid, Sinoatrial, Super protein, Potassium Inwardly-Rectifying Channel, sp, Carotid Sinus, genetic, atrioventricular block (disease), Hek 293T, Novel, Methodological Studies, Ionic Channel, Transmembrane Potentials, atrioventricular block, 7q21.1, Family Life Cycles, Heterozygote, BCNG2, Long-Term Effects, activation., Oocyte, TS, Gene Mutant, PROTEIN SUBUNIT, Sindhi Language, Computer Programming Object Property, Effort, wide/broad, LQT8, gyltl1b-b, African clawed frog, Native, MELC-CC, Sinoatrial Nodes, D-Ets-2, ets94F, common platanna, Atrioventricular Conduction ECG Assessment, 0123/09, results, Postural Syncopes, Gene Expression, MDDGA6, AVB, atrio-ventricular bundle, CCHL1A1, Atrioventricular Blocks, DNA Sequence Alteration, Diseases, Carotid Sinus Syncope, EPH-like kinase 4, Genetic Linkage Analysis, Genetic Materials, Tussive Syncopes, Adverse Event Definitely Related to Intervention, Adverse Event Related to Intervention, AV nodal block, KIAA0609, Filiation, Genetic Material, acetylglucosaminyltransferase-like 1A, Light-Headedness, ADCADN, Potential Differences, gyltl1b, positional polypeptide feature, artificial pacemaker, UNQ203/PRO229, Stimulation, Syncopal Episode, DNA (cytosine-5-)-methyltransferase 1, Channels, Effort Syncope, mdc1d, Situational, Control, Exist, hEK4, Membrane Channels, LARGE_HUMAN, Methodological Study, 293 T, lightheadedness, Heart Rate, Gene Locus, ptd, Identified, Life Cycles, disease, PntP2, Stimulating, wide, bundle of His, atrioventricular fasciculus, Expressed, Resting Potentials, PntP1, E(E2F)3D, Nodes, HEK, Episode, Cistron, Gene Variant, inherited genetic, PNTP2, Resting Membrane Potentials, Sinuatrial Nodes, Tyrosine-protein kinase receptor ETK1, Fainting spell, Transcriptome Sequencings, PNTP1, AT1G11140, heterotrimeric G-protein GTPase activity, other disease, Transmembrane, Family Member, Procedures, 293tsA1609neo, Complete Exome, ETS2, Ets2, heterotrimeric G-protein GTPase, AVCOND, SA node, Gene, Drop Attacks, Network, broad, Potential Difference, Compare, froggy, Gyltl1a, CG12298, 293T, Presyncope, rate of heart contraction, pntegfr, dizzy, HAC1, 0608/07, HEK4, Syncopal, reduced, Relations, Chronotropy, Passage, Drop, Cardiac Chronotropy, Sindhi, Studies, Thing Owned, Stimulated, tiny, AV Block, Ionic, Gnb-2, Tyrosine-protein kinase TYRO4, BX647543, WES, log, Hyperventilation Syncope, Hyperventilation Syncopes, Couple, Genetic, 293-T, Research, Transmembrane Potential, Being, Dynamics Simulations, Autosomal dominant form, LARGE, Molecular Dynamics Simulations, Lassitude, non-neoplastic, BPFD#36, Blocks, Mif1, AV bundle, 2.7.10.1, SA nodal muscle tissue, Atrioventricular Conduction Blocks, Deglutitional, disorder, SRF9, Long-Term Effect, Membrane Channel, Kinship Networks, Drop Attack, Known, Family, l(3)j1B7, DNA MTase HsaI, small, Stokes Adams, Human Embryonic Kidney 293T, GENETIC_SEQ, protein complex, DNMT, Targeted, Micturition, HEK 293 T, Sinu-Atrial Nodes, Certain, medical condition, Cistrons, Related Attribution, STRUBBELIG-RECEPTOR FAMILY 9, Simulations, Released, Syncopes, Channel, Sinuatrial, Micturition Syncopes, DNA methyltransferase HsaI, Protein, KCNJ5 wt Allele, Pulse Rate, Objective, sequence, techniques, Heartbeat, Block, l(3)s118306, ICDC Property Terminology, Rare Disease, pacemaker, sinuatrial nodal muscle tissue, Stokes-Adams Syncopes, Complete Transcriptome Sequencing, CACN2, Resting, Reason, Dizziness, FLO10, pathophysiology, Membrane, HERP, Release, Protein Gene Products, Cardiac Rate, Ets58AB, Heart Rates, Pulse, sinoatrial node, alternative, Ion, Sino-Atrial Node, Rare Diseases, Attack, SNAP, Kir3.4, Potentials, Simulation, Rate Control, D930026N18Rik, alpha-subunit, Clinical Trial Objective, T19D16.8, locus, SCM, HEK-293-T, m.HsaI, glycosyltransferase-like protein LARGE1, methodologyfalseena-DATASET-IfGH-11-05-2017-08:36:08:072-67 - samplesClinical and genetic information of an individual with RVOT-VT and a KCNK2 (TREK1) gene mutation obtained after whole exome sequencing.2017-07-26 15:39:29EGAD00001003328960628219978EGAC00001000621EGAS00001002319