HBEGF, SRA1, and IK: Three co-segregating genes as determinants of cardiomyopathy
- Frauke Friedrichs1,
- Christian Zugck2,
- Gerd-Jorg Rauch2,
- Boris Ivandic2,
- Dieter Weichenhan2,
- Margit Muller-Bardorff3,
- Benjamin Meder2,
- Nour Eddine El Mokhtari4,
- Vera Regitz-Zagrosek5,
- Roland Hetzer5,
- Arne Schafer6,
- Stefan Schreiber6,
- Jian Chen7,
- Isaac Neuhaus7,
- Ruiru Ji7,
- Nathan O. Siemers7,
- Norbert Frey2,
- Wolfgang Rottbauer2,
- Hugo A. Katus2, and
- Monika Stoll1,8
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.
Footnotes
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- Received January 29, 2008.
- Accepted December 3, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press
