Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes

Hum Mol Genet. 2019 Jul 1;28(13):2212-2223. doi: 10.1093/hmg/ddz053.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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*