Table 1.
Summary of reports modeling maturity-onset diabetes of the young (MODY) mutation effects.
| Gene studied | Pancreatic defects reported in humans | Effects recapitulated in mice | Genome editing approach | Differentiation protocol | Type of human pluripotent stem cell | In vitro phenotypes | Ref. |
|---|---|---|---|---|---|---|---|
| HNF4A (MODY1) | HNF4A heterozygous mutations affect both liver and pancreas development. MODY1 patients present neonatal hyperinsulinemia and impairment in β cell function. They present normal insulin sensitivity but decreased insulin secretion. | Rodent models do not accurately recapitulate the MODY1 phenotype in humans. The available Hnf4a general knockout murine model is embryonic lethal, while heterozygous mice present normal glucose tolerance and do not show any diabetic features. | NA | (62) | hiPSCs were derived from MODY1 mutation carriers. Their family members, without the mutation, were used as controls. | The HNF4A mutation studied did not prevent the formation of insulin+ cells in vitro. Also, no defects in β-like cells differentiated from HNF4A mutant hiPSCs were found. | (105) |
| NA | Adapted from (62). | Control hiPSC lines (CSES7 and IPSO lines) and MODY1 patient-derived hiPSCs. | Researchers report that cells from the MPC stage show increased expression of endocrine progenitor transcription factors, including PAX6, NEUROD1 and NEUROG3. | (106) | |||
| Site-directed mutagenesis. | (61) | hiPSCs were derived from non-diabetic and MODY1 patients. | Key developmental genes such as HNF1B, PDX1, GATA4, and RFX6 are downregulated at the foregut progenitor stage, prior to MPC specification. Still, terminally differentiated β-like cells can be produced and express selective β cell markers and C-peptide. The functional capacity of these cells could not be appropriately elucidated due to limitations of the in vitro protocol used. | (107) | |||
| GCK (MODY2) | Patients with GCK heterozygous mutations present progressive β-cell dysfunction, fasting hyperglycemia and reduced insulin secretion. These result in a mild diabetes phenotype that generally does not require anti-diabetes medication. | Homozygous mutant mice exhibit growth retardation and die soon after birth as consequence of severe hyperglycemia. Heterozygous mutant mice only present slightly elevated blood glucose levels from birth, with disturbed glucose tolerance and glucose-induced insulin secretion. | NA | NA | Non-edited MODY2 and PNDM patient-derived hiPSCs. | This work reports the generation of iPSCs from MODY2 patients. The researchers did not analyze differentiation into the pancreatic lineage. | (108) |
| HNF1A (MODY3) | Patients with HNF1A heterozygous mutations show β cell dysfunction and hyperglycemia due to insufficient insulin release in response to increased blood glucose levels. | Mouse models do not fully mimic the human disease phenotype. Mice with heterozygous mutations in Hnf1a are healthy and mice with homozygous null mutations present a diabetic phenotype. | CRISPR-CAS9 system. | (62), with minor modifications. | Genome-edited hESCs (MEL1 and H1) and human β-cell lines (EndoC-BH). | Differentiation from HNF1A +/- hESC show reduced number of INS+ cells. β-like cells present defects in mitochondrial function and the glycolysis process. Decreased expression of β cell transcription factors and genes associated with insulin synthesis. Reduced β cell proliferation and increased apoptosis. | (109) |
| NA | (61), with some modifications. | hiPSCs were derived from MODY3 patients. hiPSCs derived from a healthy donor were used as control. | HNF1A MODY3 mutations caused decreased GLUT2 expression, which was associated with reduced glucose uptake and ATP production. The mutant HNF1A β-like cells present decreased insulin secretion in response to high glucose. | (110) | |||
| PDX1 (MODY4) | PDX1 heterozygous mutations are associated with insulin secretion deficiency. Common point heterozygous mutations in the PDX1 transactivation domain impair human pancreatic β cell formation and function, and contribute to increased risk for diabetes. Pancreatic developmental anomalies related to PDX1 mutations are reported only in neonatal diabetes cases. | Homozygous Pdx1-deficient mice fail to generate a pancreas, while heterozygous animals develop a pancreas but become diabetic in adulthood due to β cell apoptosis. | TALEN and CRISPR/Cas9. | Adapted from (52, 54). | Genome-edited hESCs (HUES8). | Monoallelic PDX1 mutations are associated with decreased PDX1 protein expression. These compromise endocrine differentiation and lead to reduction in the number of INS+ cells derived in vitro. | (111) |
| CRISPR/Cas9. | Based on (62). | Genome-edited hiPSCs and patient-derived hiPSCs. | Heterozygous mutations impair in vitro β cell differentiation and function. Homozygous point mutations in the PDX1 transactivation domain do not only impact pancreatic endocrine lineage development, but also impair glucose-responsive function of β cells through misregulation of several PDX1 target genes. | (112) | |||
| HNF1B (MODY5) | Patients with HNF1B heterozygous mutations commonly exhibit pancreatic hypoplasia, β-cell dysfunction and insulin resistance. | Hnf1b-/- mice present pancreatic agenesis, exhibiting loss of expression of several pancreatic genes, including Pax6, which regulate β-cell function. In contrast with MODY5 patients, Hnf1b +/- mice do not develop diabetes. | NA | Adapted from (52). | MODY5 patient-derived hiPSCs. | Upregulation of multiple key pancreatic transcription factors at the DE and MPC stage, including FOXA2, PDX1, GATA4 and GATA6. Interestingly, expression of HNF1B itself was induced in mutant hiPSC-derived MPCs. Reduction of PAX6 expression. | (113) |
NA, not applicable.