PUBLICATION

A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene.

Authors
Ding, Y., Long, P.A., Bos, J.M., Shih, Y.H., Ma, X., Sundsbak, R.S., Chen, J., Jiang, Y., Zhao, L., Hu, X., Wang, J., Shi, Y., Ackerman, M.J., Lin, X., Ekker, S.C., Redfield, M.M., Olson, T.M., Xu, X.
ID
ZDB-PUB-160920-5
Date
2016
Source
JCI insight   1(14): (Journal)
Registered Authors
Ding, Yonghe, Ekker, Stephen C., Lin, Xueying, Ma, Xiao, Shih, Yu-huan, Xu, Xiaolei
Keywords
Cardiology, Genetics
MeSH Terms
none
PubMed
27642634 Full text @ JCI Insight
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes
This article is corrected by ZDB-PUB-220906-68.