A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

Yonghe Ding, Pamela A. Long, J. Martijn Bos, Yu Huan Shih, Xiao Ma, Rhianna S. Sundsbak, Jianhua Chen, Yiwen Jiang, Liqun Zhao, Xinyang Hu, Jianan Wang, Yongyong Shi, Michael J. Ackerman, Xueying Lin, Stephen C. Ekker, Margaret M. Redfield, Timothy M. Olson, Xiaolei Xu

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 (dnajb6b(L)) was identified as a CM susceptibility gene, supported by identification of rare variants in its human ortholog DNAJB6 from CM patients. Mechanistic studies indicated that the deleterious, loss-of-function modifying effects of dnajb6b(L) can be ameliorated by inhibition of ER stress. In contrast, overexpression of dnajb6(L) 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.

Original languageEnglish (US)
Article numbere88797
JournalJournal of Clinical Investigation
Volume1
Issue number14
DOIs
StatePublished - Sep 8 2016

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene'. Together they form a unique fingerprint.

Cite this