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JCI Insight. 2016 Sep 8;1(14). pii: e88797.

A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene.

Author information

1
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
2
Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
3
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA.
4
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
5
Department of Cardiology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
6
Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China.
7
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
8
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
9
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
10
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
11
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA; Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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.

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