Key result
A phenotype-based forward genetic screen in zebrafish and mouse models identified Dnajb6 as a novel causative gene for sick sinus syndrome.
Why the study?
Partially due to aging-associated phenotypic manifestation and low expressivity, the molecular mechanisms and essential genes underlying sick sinus syndrome remain difficult to decipher.
A forward genetic screen in zebrafish identified Dnajb6 as a novel causative gene for sick sinus syndrome, highlighting the heterogeneity of cardiac pacemaker cells.
Answers are grounded in this paper and cite their sources.
Zebrafish screen nominates SSS gene candidates; leaves open human translation pending validation.
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.
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Ding et al. (2022) studied Sick sinus syndrome. Dnajb6 mutation was evaluated on Identification of SSS causative genes. A phenotype-based forward genetic screen in zebrafish and mouse models identified Dnajb6 as a novel causative gene for sick sinus syndrome.
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