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HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy

By Frauke Friedrichs, Christian Zugck, Gerd-Jörg Rauch, Boris Ivandic, Dieter Weichenhan, Margit Müller-Bardorff, Benjamin Meder, Nour Eddine El Mokhtari, Vera Regitz-Zagrosek, Roland Hetzer, Arne Schäfer, Stefan Schreiber, Jian Chen, Isaac Neuhaus, Ruiru Ji, Nathan O. Siemers, Norbert Frey, Wolfgang Rottbauer, Hugo A. Katus and Monika Stoll

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

Topics: Letter
Publisher: Cold Spring Harbor Laboratory Press
OAI identifier: oai:pubmedcentral.nih.gov:2661798
Provided by: PubMed Central
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