| First Author | Ding Y | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 36255053 | Mgi Jnum | J:331268 |
| Mgi Id | MGI:7386456 | Doi | 10.7554/eLife.77327 |
| Citation | Ding Y, et al. (2022) A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene. Elife 11 |
| abstractText | Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish (<i>Danio rerio</i>) 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, <i>GBT411</i>, in both zebrafish and mouse models unveiled <i>Dnajb6</i> 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. |
