Molecular impact of a novel HNF1B missense variant in childhood-onset MODY5: a case report and functional study

Maturity-onset diabetes of the young type 5 (MODY5) is a rare autosomal-dominant monogenic diabetes caused by functional loss of the transcription factor, hepatocyte nuclear factor-1 beta (HNF1B). Although numerous HNF1B variants have been reported, the molecular mechanisms underlying the wide phenotypic variability-particularly among missense variants-remain incompletely understood. In this report, we describe a 12-year-old Japanese female with early-onset diabetes mellitus, pancreatic hypoplasia, and multiple renal cysts, harboring a novel de novo HNF1B missense variant (p.Met160Thr) located within the POU-specific domain. This early multisystem presentation highlights the clinical relevance of variants affecting this domain. Through in vitro analyses, including electrophoretic mobility shift assays, circular dichroism spectroscopy, and luciferase reporter assays, we demonstrate that the p.Met160Thr variant results in structural alterations, impaired DNA-binding stability, and markedly reduced transcriptional activity. Importantly, our data indicate that this variant acts via haploinsufficiency rather than a dominant-negative mechanism and disrupts normal HNF1A-mediated transcriptional function. These findings expand current understanding of genotype-phenotype correlations in MODY5 and emphasize the importance of early genetic testing in pediatric patients with antibody-negative diabetes.