title: A Mutation in the G-Protein GeneGNB2Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  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 theGNB2gene that strictly cosegregated with the SND+AVB phenotype.GNB2encodes the β2subunit (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 andXenopus laevisoocytes), an enhanced activation of the G-protein-activated K+channel (GIRK; Kir3.1/Kir3.4) was shown when mutant Gβ2was coexpressed with Gγ2; this was in contrast to coexpression of mutant Gβ2-Gγ2with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ2to cardiac GIRK channels when compared with native Gβ2.
  
  
  CONCLUSIONS
  AGNB2gene 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.
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuß
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Kotthoff
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Sven
authors.initials: S
authors.lastname: Zumhagen
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Kirsty
authors.initials: K
authors.lastname: Vowinkel
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Susanne
authors.initials: S
authors.lastname: Rinné
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Lina A
authors.initials: LA
authors.lastname: Matschke
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Corinna
authors.initials: C
authors.lastname: Friedrich
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Schulze-Bahr
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.affiliation: From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.). eric.schulze-bahr@ukmuenster.de.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D054537:Atrioventricular Block / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012804:Sick Sinus Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D012849:Sinoatrial Node / Q000502:physiology; D055815:Young Adult
chemical_list: C578133:GNB2 protein, human; D019204:GTP-Binding Proteins
keywords: atrial fibrillation; atrioventricular block; bradycardia; dizziness; sick sinus syndrome