A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene

• DOI: 10.7554/elife.77327
• Publication Date: 2022-10-18T10:15:15Z
• Authors: Yonghe Ding; Di Lang; Jianhua Yan; Haisong Bu; Hongsong Li; Kunli Jiao; Jingchun Yang; Haibo Ni; Stefano Morotti; Tai Le; Karl J Clark; Jenna Port; Stephen C Ekker; Hung Cao; Yuji Zhang; Jun Wang; Eleonora Grandi; Zhiqiang Li; Yongyong Shi; Yigang Li; Alexey V Glukhov; Xiaolei Xu
• Keywords: 570; Biomedical and clinical sciences; QH301-705.5; Science; Bioinformatics and Computational Biology; 610; Nerve Tissue Proteins; sinus arrest; Arrhythmias; electrocardiogram; Cardiovascular; Mice; Electrocardiography; genetic diseases; sick sinus syndrome; Genetics; genomics; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; 2.1 Biological and endogenous factors; Animals; Humans; genetics; Biology (General); Zebrafish; Sinoatrial Node; Sick Sinus Syndrome; Biomedical and Clinical Sciences; Q; R; Health sciences; Genetics and Genomics; Arrhythmias, Cardiac; Biological Sciences; HSP40 Heat-Shock Proteins; Dnajb6; zebrafish; Biological sciences; Heart Disease; Phenotype; Medicine; Biochemistry and Cell Biology; Cardiac; Molecular Chaperones

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.