PUBLICATION
Genome-edited zebrafish model of ABCC8 loss-of-function disease
- Authors
- Ikle, J.M., Tryon, R.C., Singareddy, S.S., York, N.W., Remedi, M.S., Nichols, C.G.
- ID
- ZDB-PUB-221203-4
- Date
- 2022
- Source
- Islets 14: 200209200-209 (Journal)
- Registered Authors
- Nichols, Colin G., Tryon, Robert, York, Nathaniel
- Keywords
- KATP, calcium channels, insulin secretion, metabolism, pancreas, zebrafish
- MeSH Terms
-
- Adenosine Triphosphate
- Animals
- Disease Models, Animal
- Glucose Intolerance*
- Hyperinsulinism*
- Mice
- Mice, Knockout
- Mice, Transgenic
- Sulfonylurea Receptors/genetics
- Zebrafish/genetics
- PubMed
- 36458573 Full text @ Islets
Citation
Ikle, J.M., Tryon, R.C., Singareddy, S.S., York, N.W., Remedi, M.S., Nichols, C.G. (2022) Genome-edited zebrafish model of ABCC8 loss-of-function disease. Islets. 14:200209200-209.
Abstract
ATP-sensitive potassium channel (KATP)gain- (GOF) and loss-of-function (LOF) mutations underlie human neonatal diabetes mellitus (NDM) and hyperinsulinism (HI), respectively. While transgenic mice expressing incomplete KATP LOF do reiterate mild hyperinsulinism, KATP knockout animals do not exhibit persistent hyperinsulinism. We have shown that islet excitability and glucose homeostasis are regulated by identical KATP channels in zebrafish. SUR1 truncation mutation (K499X) was introduced into the abcc8 gene to explore the possibility of using zebrafish for modeling human HI. Patch-clamp analysis confirmed the complete absence of channel activity in β-cells from K499X (SUR1-/-) fish. No difference in random blood glucose was detected in heterozygous SUR1+/- fish nor in homozygous SUR1-/- fish, mimicking findings in SUR1 knockout mice. Mutant fish did, however, demonstrate impaired glucose tolerance, similar to partial LOF mouse models. In paralleling features of mammalian diabetes and hyperinsulinism resulting from equivalent LOF mutations, these gene-edited animals provide valid zebrafish models of KATP -dependent pancreatic diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping