A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

Abstract

Mutagenesis screening is a powerful forward genetic approach that has been successfully applied in lower-model organisms to discover genetic factors for biological processes. This phenotype-based approach has yet to be established in vertebrates for probing major human diseases, largely because of the complexity of colony management. Herein, we report a rapid strategy for identifying genetic modifiers of cardiomyopathy (CM). Based on the application of doxorubicin stress to zebrafish insertional cardiac (ZIC) mutants, we identified 4 candidate CM-modifying genes, of which 3 have been linked previously to CM. The long isoform of DnaJ (Hsp40) homolog, subfamily B, member 6b (<i>dnajb6b(L)</i>) was identified as a CM susceptibility gene, supported by identification of rare variants in its human ortholog <i>DNAJB6</i> from CM patients. Mechanistic studies indicated that the deleterious, loss-of-function modifying effects of <i>dnajb6b(L)</i> can be ameliorated by inhibition of ER stress. In contrast, overexpression of <i>dnajb6(L)</i> exerts cardioprotective effects on both fish and mouse CM models. Together, our findings establish a mutagenesis screening strategy that is scalable for systematic identification of genetic modifiers of CM, feasible to suggest therapeutic targets, and expandable to other major human diseases.