@article{945178045b154f7f892cf42030e12930,
title = "A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene",
abstract = "Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish (Danio rerio) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for discovering essential genes for heart rhythm disorders such as sick sinus syndrome (SSS). SSS is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart{\textquoteright}s primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. From 609 GBT lines screened, we generated a collection of 35 zebrafish insertional cardiac (ZIC) mutants in which each mutant traps a gene with cardiac expression. We further employed electrocardiographic measurements to screen these 35 ZIC lines and identified three GBT mutants with SSS-like phenotypes. More detailed functional studies on one of the arrhythmogenic mutants, GBT411, in both zebrafish and mouse models unveiled Dnajb6 as a novel SSS causative gene with a unique expression pattern within the subpopulation of sinus node pacemaker cells that partially overlaps with the expression of hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4), supporting heterogeneity of the cardiac pacemaker cells.",
author = "Yonghe Ding and Di Lang and Jianhua Yan and Haisong Bu and Hongsong Li and Kunli Jiao and Jingchun Yang and Haibo Ni and Stefano Morotti and Tai Le and Clark, {Karl J.} and Jenna Port and Ekker, {Stephen C.} and Hung Cao and Yuji Zhang and Jun Wang and Eleonora Grandi and Zhiqiang Li and Yongyong Shi and Yigang Li and Glukhov, {Alexey V.} and Xiaolei Xu",
note = "Funding Information: We thank Beninio Gores and Kashia Stragey for managing zebrafish facility and Ronald H May for murine echocardiography. This work was supported in part by Mayo Foundation to XX, grant from Science and Technology Innovation Action Plan of Shanghai, experimental animal research project 201409005600 to YGL, NIH GM063904 to SCE, NIH R01HL141214, American Heart Association 16SDG29120011, and the Wisconsin Partnership Program 4140 to AVG, American Heart Association 17POST33370089 and American Heart Association Career Development Award 846898 to DL, NIH R00HL138160 to SM, NIH R01HL131517, NIH P01HL141084 NIH Stimulating Peripheral Activity to Relieve Conditions Grant 1OT2OD026580-01, UC Davis School of Medicine Dean{\textquoteright}s Fellow Award, and American Heart Association Scientist Development Award 15SDG24910015 to EG, and American Heart Association Postdoctoral Fellowship 20POST35120462 to HN, NIH R44OD024874 to TL and HC, NIH R01HL142704 to JW. Funding Information: We thank Beninio Gores and Kashia Stragey for managing zebrafish facility and Ronald H May for murine echocardiography. This work was supported in part by Mayo Foundation to XX, grant from Science and Technology Innovation Action Plan of Shanghai, experimental animal research project 201409005600 to YGL, NIH GM063904 to SCE, NIH R01HL141214, American Heart Association 16SDG29120011, and the Wisconsin Partnership Program 4140 to AVG, American Heart Association 17POST33370089 and American Heart Association Career Development Award 846898 to DL, NIH R00HL138160 to SM, NIH R01HL131517, NIH P01HL141084 NIH Stimulating Peripheral Activity to Relieve Conditions Grant 1OT2OD026580-01, UC Davis School of Medicine Dean{\textquoteright}s Fellow Award, and American Heart Association Scientist Development Award 15SDG24910015 to EG, and American Heart Association Postdoctoral Fellowship 20POST35120462 to HN, NIH R44OD024874 to TL and HC, NIH R01HL142704 to JW. Mayo Foundation for Medical Education and Research Xiaolei Xu Science and Technology Innovation Action Plan of Shanghai 201409005600 Yigang Li National Institute of Health GM063904 Stephen C Ekker American Heart Association 16SDG29120011 Alexey V Glukhov National Institute of Health R00HL138160 National Institute of Health R01HL131517 Stefano Morotti Eleonora Grandi American Heart Association 15SDG24910015 Eleonora Grandi American Heart Association 20POST35120462 Haibo Ni National Institute of Health NIH R01HL141214 Alexey V Glukhov Wisconsin Partnership Program 4140 Alexey V Glukhov American Heart Association 17POST33370089 Di Lang American Heart Association 846898 Di Lang National Institute of Health 1OT2OD026580-01 National Institute of Health P01HL141084 Eleonora Grandi Eleonora Grandi National Institutes of Health R44OD024874 Tai Le National Institutes of Health R44OD024874 Hung Cao National Institutes of Health R01HL142704 Jun Wang The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} Ding et al.",
year = "2022",
doi = "10.7554/eLife.77327",
language = "English (US)",
volume = "11",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}