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
-
- Alstrom Syndrome/genetics*
- Alstrom Syndrome/physiopathology
- Animals
- Animals, Genetically Modified
- Cell Line
- Diabetes Mellitus, Type 2/genetics*
- Disease Models, Animal
- Glucose Intolerance
- Hyperinsulinism/genetics
- Insulin Resistance/genetics*
- Insulin-Secreting Cells/metabolism
- Mice
- Models, Biological
- Obesity/genetics
- Phenotype
- Renal Insufficiency/genetics*
- Retinal Degeneration/genetics*
- Zebrafish/embryology
- Zebrafish/genetics*
- PubMed
- 31220269 Full text @ Hum. Mol. Genet.
Citation
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. (2019) Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes. Human molecular genetics. 28:2212-2223.
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