title: A modifier screen identifiesDNAJB6as 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 (dnajb6b(L)) was identified as a CM susceptibility gene, supported by identification of rare variants in its human orthologDNAJB6from CM patients. Mechanistic studies indicated that the deleterious, loss-of-function modifying effects ofdnajb6b(L)can be ameliorated by inhibition of ER stress. In contrast, overexpression ofdnajb6(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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Long
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yu-Huan
authors.initials: YH
authors.lastname: Shih
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Rhianna S
authors.initials: RS
authors.lastname: Sundsbak
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China.
authors.forename: Jianan
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ekker
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
authors.affiliation: 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.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Xu