Huttner, Inken G. and Santiago, Celine F. and Jacoby, Arie and Cheng, Delfine and Trivedi, Gunjan and Cull, Stephen and Cvetkovska, Jasmina and Chand, Renee and Berger, Joachim and Currie, Peter D. and Smith, Kelly A. and Fatkin, Diane (2023) Loss of Sec-1 Family Domain-Containing 1 (scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish. Journal of Cardiovascular Development and Disease, 10 (10). p. 408. ISSN 2308-3425
Full text not available from this repository.Abstract
Dilated cardiomyopathy (DCM) is a common heart muscle disorder that frequently leads to heart failure, arrhythmias, and death. While DCM is often heritable, disease-causing mutations are identified in only ~30% of cases. In a forward genetic mutagenesis screen, we identified a novel zebrafish mutant, heart and head (hah(vcc43)), characterized by early-onset cardiomyopathy and craniofacial defects. Linkage analysis and next-generation sequencing identified a nonsense variant in the highly conserved scfd1 gene, also known as sly1, that encodes sec1 family domain-containing 1. Sec1/Munc18 proteins, such as Scfd1, are involved in membrane fusion regulating endoplasmic reticulum (ER)/Golgi transport. CRISPR/Cas9-engineered scfd1(vcc44) null mutants showed severe cardiac and craniofacial defects and embryonic lethality that recapitulated the phenotype of hah(vcc43) mutants. Electron micrographs of scfd1-depleted cardiomyocytes showed reduced myofibril width and sarcomere density, as well as reticular network disorganization and fragmentation of Golgi stacks. Furthermore, quantitative PCR analysis showed upregulation of ER stress response and apoptosis markers. Both heterozygous hah(vcc43) mutants and scfd1(vcc44) mutants survived to adulthood, showing chamber dilation and reduced ventricular contraction. Collectively, our data implicate scfd1 loss-of-function as the genetic defect at the hah(vcc43) locus and provide new insights into the role of scfd1 in cardiac development and function.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 01 May 2024 04:33 |
| Last Modified: | 01 May 2024 04:33 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1464 |
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