MODY3 Diabetes

DefiniGEN MODY3 Diabetes human pancreatic cells display a mutation in the HNF1-alpha transcription factor gene, specifically an insertion of C at codon 872 producing a frameshift mutation. MODY3 (also known as HNF1a-MODY) is caused by mutations in the HNF1-alpha gene which is a key regulatory transcription factor controlling the downstream regulation of multiple genes involved in the differentiation of beta cells. These cell products can empower disease modelling and drug discovery researchers with unique tools for use in mechanistic studies of MODY. Our custom services can also engineer bespoke mutations for additional forms of the eleven known types of MODY.

• Highly standardized cell product containing >97% human pancreatic cells with consistent performance and biologically relevant data
• Disease circuit verified confirmed mutation in the HNF1-alpha transcription factor gene – insertion of C at codon 872 producing a frameshift mutation
• Phenotypic analysis of the cells using GSIS assays demonstrates that the insulin response to glucose challenge is dysfunctional in these disease modelled cell products in contrast to DefiniGEN’s isogenic wild-type control pancreatic cell products.

Def-PANC MODY3 Cell Morphology

In contrast to Def-PANC WT cells which display normal tightly packed pancreatic cell morphology. Def-PANC MODY3 cells display aberrant morphology expected from developmental retardation caused by the HNF1a mutation.

Figure 1. Def-PANC MODY3 cell morphology. The homozygous Def-PANC MODY3 disease modelled cells display aberrant morphology in both monolayer and micro-islet culture.

Disease circuit verification

MODY3 pancreatic disease model with mutation in HNF1-alpha transcription factor gene – insertion of C at codon 872 producing frameshift mutation – isogenic control available.

Figure 2. Sanger sequencing of Def-PANC MODY3 mutation. The sequence analysis shows heterozygous HNF1a with single base insertion of a C in a polyC tract codon 291 for Proline.

GLUT + PKLR Expression Analysis

The expected down regulation of pancreatic cell function gene sets is observed in Def-PANC MODY3 cells in both the disease model variants.

Figure 3. Down regulation of key genes in Def-PANC MODY3 cells. Heterozygous and homozygous Def-PANC MODY3 cells show progressive gene change effects in key HNF1a gene regulated including PKLR and GLUT-2.

Pancreatic Key Marker Analysis

The expression of crucial pancreatic genes in sequentially reduced in disease modelled Def-PANC cells.

Figure 4. Def-PANC MODY3 cell marker analysis. QPCR analysis shows the expected reduction in key pancreatic cell markers in the Def-PANC disease models with a gene dosage dependent effect being observed.