title: HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy.
abstract: Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary.
authors.affiliation: Division of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, Heidelberg 69120, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Friedrichs
authors.forename: Christian
authors.initials: C
authors.lastname: Zugck
authors.forename: Gerd-Jörg
authors.initials: GJ
authors.lastname: Rauch
authors.forename: Boris
authors.initials: B
authors.lastname: Ivandic
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Margit
authors.initials: M
authors.lastname: Müller-Bardorff
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.forename: Nour Eddine
authors.initials: NE
authors.lastname: El Mokhtari
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: Roland
authors.initials: R
authors.lastname: Hetzer
authors.forename: Arne
authors.initials: A
authors.lastname: Schäfer
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Isaac
authors.initials: I
authors.lastname: Neuhaus
authors.forename: Ruiru
authors.initials: R
authors.lastname: Ji
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Siemers
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D009202:Cardiomyopathies / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D002874:Chromosome Mapping; D020090:Chromosome Segregation / Q000502:physiology*; D002895:Chromosomes, Human, Pair 5; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D004625:Embryo, Nonmammalian; D005819:Genetic Markers / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007249:Inflammation / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000502:physiology; D016277:Ventricular Function, Left / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D016207:Cytokines; D005819:Genetic Markers; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; C090444:IK protein, human; D036341:Intercellular Signaling Peptides and Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C405423:steroid receptor RNA activator