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

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.

The protein encoded by the functional steroid receptor RNA activator is a new modulator of ER alpha transcriptional activity

“…In vivo experiments showed that a decrease in SRA expression lead to a phenotype of myocardial contractile dysfunction in a zebrafish model [6], whereas an increase in mouse mammary gland stimulated proliferation and apoptosis [7]. Altogether, SRA is suspected to participate in normal and pathological events such as tissue differentiation and tumorigenesis.…”

The genetics of cardiovascular disease: new insights from emerging approaches

“…This region contains a number of genes, three of which (HBEGF, SRA1 and IK) were knocked down by MO in zebrafish embryos and shown to induce DCM [92].…”

The steroid receptor RNA activator protein is recruited to promoter regions and acts as a transcriptional repressor

“…Indeed, a recent study has Table 1. shown that knocking down SRA gene led to myocardial contractile dysfunction in zebrafish, linking for the first time SRA and heart diseases [15]. The wide range of transcription factors identified as interacting with SRAP suggests that many normal and pathogenic events might involve this newly described protein.…”