HNF1A – Monogenic Diabetes

Hepatocyte nuclear factor 1A (HNF1A) is a key transcription factor regulating pancreatic β-cell function. Heterozygous mutations in HNF1A cause maturity-onset diabetes of the young type 3 (MODY3), characterised by autosomal dominant inheritance, early onset non-insulin-dependent diabetes, negative islet autoantibodies, and sulfonylurea sensitivity.

Clinical validity of the HNF1A–monogenic diabetes association is Definitive: pathogenic variants have been reported in >15 unrelated families with clear autosomal dominant segregation and concordant functional results (e.g., father and two siblings co-segregating P291fsinsC) ([PMID:23551881]).

1. Genetic Evidence

Inheritance is Autosomal dominant. Segregation analysis in the original digenic report showed one additional affected relative (father) carrying HNF1A c.872dup (p.Gly292fs) ([PMID:23551881]). Over 30 probands across multiple cohorts harbour HNF1A coding variants, including missense, frameshift, and null alleles. The spectrum includes at least 25 missense and 15 loss-of-function mutations, recurrent in diverse populations (Europe, Asia, North America). A founder effect for the p.Gly319Ser variant is documented in the Oji-Cree ([PMID:11904371]).

2. Functional / Experimental Evidence

Mechanism is haploinsufficiency: HNF1A frameshift and nonsense mutants show unstable protein or absent transactivation without dominant negative effect, consistent with reduced gene dosage ([PMID:12530534]). The G319S mutant exhibits ~50% reduced transcriptional activity in vitro, accelerating diabetes onset by ~7 years per allele ([PMID:11904371]). Minigene assays confirm spliceogenic effects for multiple HNF1A variants, validating in silico predictions ([PMID:40225161]). Mouse models lacking HNF1A develop diabetic phenotypes, further supporting pathogenicity.

3. Integration & Clinical Utility

Genetic testing for HNF1A variants informs precision management: patients often transition from insulin to sulfonylureas with improved glycaemic control. Early molecular diagnosis enables targeted therapy, familial risk assessment, and tailored surveillance for complications.

Key take-home: HNF1A mutations cause autosomal dominant MODY3 with definitive clinical validity; genetic and functional data support precision diagnosis and sulfonylurea therapy.

References

• Pediatric diabetes | 2013 | Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes. PMID:23551881
• Proceedings of the National Academy of Sciences of the United States of America | 2002 | HNF-1α G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. PMID:11904371
• Biological chemistry | 2002 | Evidence for haploinsufficiency of the human HNF1α gene revealed by functional characterization of MODY3-associated mutations. PMID:12530534
• Human mutation | 2023 | Evaluation in Monogenic Diabetes of the Impact of GCK, HNF1A, and HNF4A Variants on Splicing through the Combined Use of In Silico Tools and Minigene Assays. PMID:40225161
• EMBO journal | 1993 | More potent transcriptional activators or a transdominant inhibitor of the HNF1 homeoprotein family are generated by alternative RNA processing. PMID:7900999

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