PUBLICATION

Loss of Sec-1 Family Domain-Containing 1 (scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish

Authors
Huttner, I.G., Santiago, C.F., Jacoby, A., Cheng, D., Trivedi, G., Cull, S., Cvetkovska, J., Chand, R., Berger, J., Currie, P.D., Smith, K.A., Fatkin, D.
ID
ZDB-PUB-231028-53
Date
2023
Source
Journal of cardiovascular development and disease   10(10): (Journal)
Registered Authors
Berger, Joachim, Chand, Renee, Currie, Peter D., Fatkin, Diane, Huttner, Inken, Trivedi, Gunjan
Keywords
ER stress, dilated cardiomyopathy, genetics, protein homeostasis, scfd1, zebrafish
MeSH Terms
none
PubMed
37887855 Full text @ J Cardiovasc Dev Dis
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 (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.
Genes / Markers
Figures
Figure Gallery (6 images)
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
vcc43
    Point Mutation
    vcc44
      Small Deletion
      1 - 2 of 2
      Show
      Human Disease / Model
      Human Disease Fish Conditions Evidence
      dilated cardiomyopathyTAS
      1 - 1 of 1
      Show
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      scfd1CRISPR1-scfd1CRISPR
      scfd1MO1-scfd1MRPHLNO
      tyrCRISPR54-tyrCRISPR
      1 - 3 of 3
      Show
      Fish
      Antibodies
      Orthology
      No data available
      Engineered Foreign Genes
      No data available
      Mapping
      No data available