PUBLICATION

Differential effects on β-cell mass by disruption of Bardet-Biedl Syndrome or Alstrom Syndrome genes

Authors
Lodh, S., Hostelley, T.L., Leitch, C.C., O'Hare, E.A., Zaghloul, N.A.
ID
ZDB-PUB-151024-3
Date
2016
Source
Human molecular genetics   25(1): 57-68 (Journal)
Registered Authors
Zaghloul, Norann A.
Keywords
none
MeSH Terms
  • Alstrom Syndrome/genetics*
  • Animals
  • Bardet-Biedl Syndrome/genetics*
  • Cell Death
  • Cell Proliferation
  • Disease Models, Animal
  • Glucose
  • Hyperglycemia/pathology
  • Insulin-Secreting Cells/pathology*
  • Microtubule-Associated Proteins/genetics
  • Morpholinos/genetics
  • Zebrafish
  • Zebrafish Proteins/genetics
PubMed
26494903 Full text @ Hum. Mol. Genet.
Abstract
Rare genetic syndromes characterized by early onset type 2 diabetes have revealed the importance of pancreatic β-cells in genetic susceptibility to diabetes. However, the role of genetic regulation of β-cells in disorders that are also characterized by highly penetrant obesity, a major additional risk factor, is unclear. In this study, we investigated the contribution of genes associated with two obesity ciliopathies, Bardet-Biedl Syndrome and Alstrom Syndrome, to the production and maintenance of pancreatic β-cells. Using zebrafish models of these syndromes, we identified opposing effects on production of β-cells. Loss of the Alstrom gene, alms1, resulted in a significant decrease in β-cell production whereas loss of BBS genes, bbs1 or bbs4, resulted in a significant increase. Examination of the regulatory program underlying β-cell production suggested that these effects were specific to β-cells. In addition to the initial production of β-cells we observed significant differences in their continued maintenance. Under prolonged exposure to high glucose conditions, alms1-deficient β-cells were unable to continually expand as a result of decreased proliferation and increased cell death. Although bbs1-deficient β-cells were similarly susceptible to apoptosis, the overall maintenance of β-cell number in those animals was sustained likely due to increased proliferation. Taken together, these findings implicate discrepant production and maintenance of β-cells in the differential susceptibility to diabetes found between these two genetic syndromes.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping