PUBLICATION
Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes
- Authors
- Nesmith, J.E., Hostelley, T.L., Leitch, C.C., Matern, M.S., Sethna, S., McFarland, R., Lodh, S., Westlake, C.J., Hertzano, R., Ahmed, Z.M., Zaghloul, N.A.
- ID
- ZDB-PUB-190621-9
- Date
- 2019
- Source
- Human molecular genetics 28: 2212-2223 (Journal)
- Registered Authors
- McFarland, Rebecca, Zaghloul, Norann A.
- Keywords
- none
- MeSH Terms
-
- Insulin Resistance/genetics*
- Glucose Intolerance
- Renal Insufficiency/genetics*
- Models, Biological
- Disease Models, Animal
- PubMed
- 31220269 Full text @ Hum. Mol. Genet.
Abstract
Alström syndrome (OMIM #203800) is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early-onset type 2 diabetes mellitus (T2DM). To investigate the underlying mechanisms of T2DM phenotypes, we generated a loss-of-function deletion of alms1 in the zebrafish. We demonstrate conservation of hallmark clinical characteristics alongside metabolic syndrome phenotypes, including a propensity for obesity and fatty livers, hyperinsulinemia and glucose response defects. Gene expression changes in β-cells isolated from alms1-/- mutants revealed changes consistent with insulin hypersecretion and glucose sensing failure, which were corroborated in cultured murine β-cells lacking Alms1. We also found evidence of defects in peripheral glucose uptake and concomitant hyperinsulinemia in the alms1-/- animals. We propose a model in which hyperinsulinemia is the primary and causative defect underlying generation of T2DM associated with alms1 deficiency. These observations support the alms1 loss-of-function zebrafish mutant as a monogenic model for mechanistic interrogation of T2DM phenotypes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping