title: The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.
abstract: BACKGROUND
  Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM).
  
  
  OBJECTIVE
  The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis.
  
  
  METHODS
  The index family and a cohort of unrelated probands with sinus bradycardia were examined by electrocardiography, Holter recording, exercise stress test, echocardiography, and/or cardiac magnetic resonance imaging. Targeted next-generation and direct sequencing were used for candidate gene analysis and mutation scanning. Ion channels were expressed in HEK293 cells and studied using patch-clamp recordings.
  
  
  RESULTS
  SND and biventricular NCCM were diagnosed in multiple members of a German family. Segregation analysis suggested autosomal-dominant inheritance of the combined phenotype. When looking for potentially disease-causing gene variants with cosegregation, a novel hyperpolarization-activated cyclic nucleotide channel 4 (HCN4)-G482R mutation and a common cysteine and glycine-rich protein 3 (CSRP3)-W4R variant were identified. HCN4-G482R is located in the highly conserved channel pore domain. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current. CSRP3-W4R has previously been linked to dilated and hypertrophic cardiomyopathy, but was also found in healthy subjects. Moreover, different truncation (695X) and missense (P883R) HCN4 mutations segregated with a similar combined phenotype in an additional, unrelated family and a single unrelated proband respectively, which both lacked CSRP3-W4R.
  
  
  CONCLUSIONS
  The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany. Electronic address: patrick.schweizer@med.uni-heidelberg.de.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; Institute for Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schröter
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Greiner
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Haas
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Pessah
authors.initials: P
authors.lastname: Yampolsky
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Derliz
authors.initials: D
authors.lastname: Mereles
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Buss
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Seyler
authors.affiliation: Institute for Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Bruehl
authors.affiliation: Institute for Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Draguhn
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; Institute for Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany; Department of Molecular Neurobiology, Max-Planck-Institute for Medical Research, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Koenen
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany. Electronic address: dierk.thomas@med.uni-heidelberg.de.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
mesh_terms: D000293:Adolescent; D000818:Animals; D004452:Echocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D005858:Germany / Q000453:epidemiology; D057809:HEK293 Cells; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D015995:Prevalence; D012804:Sick Sinus Syndrome / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels
keywords: HCN4; noncompaction cardiomyopathy; overlap syndrome; sinus node dysfunction