ZFIN ID: ZDB-PUB-081218-7
HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy
Friedrichs, F., Zugck, C., Rauch, G.J., Ivandic, B., Weichenhan, D., Muller-Bardorff, M., Meder, B., El Mokhtari, N.E., Regitz-Zagrosek, V., Hetzer, R., Schafer, A., Schreiber, S., Chen, J., Neuhaus, I., Ji, R., Siemers, N.O., Frey, N., Rottbauer, W., Katus, H.A., and Stoll, M.
Date: 2009
Source: Genome research 19(3): 395-403 (Journal)
Registered Authors: Meder, Benjamin, Rauch, Gerd-Jörg, Rottbauer, Wolfgang
Keywords: complex genetics, comparative genomics, linkage disequilibrium, genomic rearrangements
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cardiomyopathies/genetics*
  • Case-Control Studies
  • Cell Line
  • Chromosome Mapping
  • Chromosome Segregation/physiology*
  • Chromosomes, Human, Pair 5
  • Cluster Analysis
  • Cytokines/genetics*
  • Cytokines/physiology
  • Embryo, Nonmammalian
  • Genetic Markers/physiology
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Inflammation/genetics
  • Intercellular Signaling Peptides and Proteins/genetics*
  • Intercellular Signaling Peptides and Proteins/physiology
  • Linkage Disequilibrium
  • Polymorphism, Single Nucleotide
  • RNA, Long Noncoding
  • RNA, Untranslated/genetics*
  • RNA, Untranslated/physiology
  • Ventricular Function, Left/genetics
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 19064678 Full text @ Genome Res.
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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 aetiology 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 aetiology of DCM (Karkkainen and Peuhkurinen 2007). We show that a 600 kilobase (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 suggests that a more detailed assessment of causality can be necessary.
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