Key result
Loss-of-function scfd1 mutations in zebrafish cause severe cardiac defects and embryonic lethality via ER stress.
Why the study?
Dilated cardiomyopathy is frequently heritable, but disease-causing mutations are identified in only ~30% of cases.
Loss of scfd1 function in zebrafish causes severe cardiac defects and ER stress, implicating it in early-onset cardiomyopathy and cardiac development.
Provides new zebrafish DCM model; hypothesis-generating for undiagnosed human cases.
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 (hahvcc43), 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 scfd1vcc44 null mutants showed severe cardiac and craniofacial defects and embryonic lethality that recapitulated the phenotype of hahvcc43 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 hahvcc43 mutants and scfd1vcc44 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 hahvcc43 locus and provide new insights into the role of scfd1 in cardiac development and function.
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Huttner et al. (2023) studied Dilated cardiomyopathy. scfd1 loss-of-function mutation was evaluated on Cardiac and craniofacial defects, embryonic lethality, and ER stress. Loss-of-function mutations in the scfd1 gene in zebrafish cause severe cardiac and craniofacial defects, embryonic lethality, and upregulation of ER stress and apoptosis markers.
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