INVESTIGATING THE EFFECTS OF A NOVEL HNF1A MUTATION IN MATURITY ONSET DIABETES OF THE YOUNG 3 (MODY3)

Abstract

Heterozygous HNF1A gene mutations can give rise to maturity onset diabetes of the young 3 (MODY3), which is characterized by insulin secretion defects. However, the specific mechanisms of MODY3 in humans remain unclear due to the lack of access to diseased human pancreatic cells. Here, I leveraged upon MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effects of a causal HNF1A(+/H126D) mutation on pancreatic β cell function. Genome-wide RNA-Seq and ChIP-Seq analyses on MODY3 hiPSC-derived endocrine progenitors revealed numerous HNF1A gene targets affected by the HNF1A(+/H126D) mutation. I found a decrease in glucose transporter GLUT2 expression, which is associated with decreased glucose uptake function and decreased ATP production in the MODY3 hiPSC-derived β-like cells. Overall, my MODY3-hiPSC-based findings reveal the importance of HNF1A in regulating GLUT2 and several genes involved in insulin secretion function that can account for the insulin secretory defect clinically observed in MODY3 patients.