HNF1A – Maturity-Onset Diabetes of the Young

Hepatocyte nuclear factor 1-alpha (HNF1A) encodes a homeodomain transcription factor essential for pancreatic β-cell development and glucose-responsive insulin secretion. Heterozygous mutations in HNF1A cause MODY3, an autosomal dominant form of monogenic diabetes presenting before age 25 with non-insulin-dependent hyperglycemia and marked sulfonylurea sensitivity.

Extensive genetic evidence supports a definitive HNF1A-MODY3 association: over 150 unrelated probands in more than 40 families have been reported with segregating HNF1A variants (PMID:18513305)( PMID:21683639). Segregation analyses reveal multiple affected relatives per pedigree, confirming autosomal dominant inheritance and fulfilling ClinGen criteria for a definitive gene–disease relationship.

Case reports and series describe a broad variant spectrum, including missense, frameshift, splice-site, promoter, and complex indel mutations. Recurrent founder alleles such as p.Arg229Gln and hotspot events at codon 292 have been observed. For example, c.815G>A (p.Arg272His) was identified in a 47-year-old MODY3 patient undergoing simultaneous pancreas–kidney transplantation (PMID:15114102).

Functional assays demonstrate that HNF1A mutations exert loss-of-function effects: many missense variants reduce DNA binding and transactivation of target promoters, consistent with haploinsufficiency (PMID:12530534). Alternative splicing of HNF1A generates isoforms with distinct transactivation domains; mutations disrupt these balances, further impairing β-cell gene regulation (PMID:7900999).

Limited conflicting evidence exists. The c.539C>T (p.Ala180Val) variant co-segregates variably with diabetes in two families without clear linkage, and shows no functional defect in vitro, suggesting it may be a risk modifier rather than a pathogenic allele (PMID:28934671).

Integration of genetic and experimental data establishes HNF1A as a definitive MODY3 gene. Genetic testing enables precision therapy—transition from insulin to sulfonylureas—and informs family screening. Key take-home: identification of pathogenic HNF1A variants delivers immediate clinical impact through tailored glucose-lowering strategies.

References

• Diabetic medicine • 2008 • Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study). PMID:18513305
• Diabetes & metabolism • 2011 • Identification of HNF1A-MODY and HNF4A-MODY in Irish families: phenotypic characteristics and therapeutic implications. PMID:21683639
• Transplantation • 2004 • Maturity-onset diabetes of the young with end-stage nephropathy: a new indication for simultaneous pancreas and kidney transplantation? PMID:15114102
• Biological chemistry • 2002 • Evidence for haploinsufficiency of the human HNF1alpha gene revealed by functional characterization of MODY3-associated mutations. PMID:12530534
• The EMBO journal • 1993 • More potent transcriptional activators or a transdominant inhibitor of the HNF1 homeoprotein family are generated by alternative RNA processing. PMID:7900999
• Diabetes research and clinical practice • 2017 • The HNF1A mutant Ala180Val: Clinical challenges in determining causality of a rare HNF1A variant in familial diabetes. PMID:28934671

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