Citations 2
Author response: A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene
Yan, Jianhua , Li, Hongsong , Jiao, Kunli , Yang, Jingchun , Port, Jenna , Wang, Jun , Li, Yi‐Gang , Ding, Yonghe , Lang, Di , Bu, Haisong , Ni, Haibo , Morotti, Stefano , Le, Tai , Clark, Karl J. , Ekker, Stephen C. , Cao, Hung , Zhang, Yuji , Grandi, Eleonora , Li, Zhiqiang , Shi, Yongyong , Glukhov, Alexey V. , Xu, Xiaolei
No container title available | November 8, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene
Ding, Yonghe , Yan, Jianhua , Li, Hongsong , Jiao, Kunli , Yang, Jingchun , Port, Jenna , Wang, Jun , Shi, Yongyong , Li, Yi‐Gang , Bu, Haisong, Clark, Karl J , Ekker, Stephen C , Lin, Xueying , Ding, Yonghe , Lang, Di , Bu, Haisong , Ni, Haibo , Morotti, Stefano , Le, Tai , Clark, Karl J. , Ekker, Stephen C. , Cao, Hung , Zhang, Yuji , Grandi, Eleonora , Li, Zhiqiang , Glukhov, Alexey V. , Xu, Xiaolei
eLife | October 18, 2022 | Volume: 11 | Issue: No issue available | Pages: No page available
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’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.