Monogenic diabetes, formerly called Maturity-Onset Diabetes of the Young (MODY), involves single-gene mutations, typically with dominant inheritance, and has been associated with variants in 14 genes. Among these, HNF1A mutations are the most common, and their diagnosis allows the use of alternative therapies, including sulfonylureas. In an earlier study, we described a variant displaying recessive transmission, p.A251T (Misra, S et al, Diabetes Care, 2020). Initial functional studies revealed only a modest impact on protein function. We extend these earlier in vitro studies to demonstrate that beta-like cells derived from pluripotent stem cells from variant carriers show impaired differentiation into insulin-positive cells, whereas differentiation into alpha cells is significantly enhanced. Additionally, mutant cells showed impaired glucose-stimulated insulin secretion but partially preserved responsiveness to treatment with sulfonylureas. Our study provides proof of principle for the utility of using patient-derived stem cells as a platform to assess the pathogenicity of HNF1A variants, and to explore potential treatment strategies.

GAR has received grant funding from and is a consultant for Sun Pharmaceuticals Inc. No other author declares a competing interest.

G.A.R. was supported by a Wellcome Trust Investigator Award (WT212625/Z/18/Z), MRC Programme grant (MR/R022259/1), Diabetes UK (BDA 16/0005485) and NIH-NIDDK (R01DK135268, 1R01DK139630-01A1) project grants, a CIHR-JDRF Team grant (CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N), CRCHUM start-up funds, and an Innovation Canada John R. Evans Leader Award (CFI 42649).

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