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

Authors:
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, Monika Stoll
Year of publication:
2009
Volume:
19
Issue:
3
Issn:
1088-9051
Journal title abbreviated:
GENOME RES
Journal title long:
Genome research
Impact factor:
11.351
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.