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.
Citation
Lodh, S., Hostelley, T.L., Leitch, C.C., O'Hare, E.A., Zaghloul, N.A. (2016) Differential effects on β-cell mass by disruption of Bardet-Biedl Syndrome or Alstrom Syndrome genes. Human molecular genetics. 25(1):57-68.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping