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.
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.