HNF4A – Maturity-Onset Diabetes of the Young

Heterozygous variants in the transcription factor HNF4A are a well-established cause of MODY1, an autosomal dominant form of monogenic diabetes characterized by β-cell dysfunction and progressive hyperglycemia. Patients typically present with insulin secretory defects in adolescence or early adulthood, and some may exhibit neonatal hyperinsulinemic hypoglycemia that evolves into diabetes (PMID:12203996). The penetrance is high in familial cases but can be reduced in population carriers of certain alleles (PMID:27486234).

Genetic evidence includes a Swiss pedigree in which a c.322G>A (p.Val108Ile) variant in HNF4A segregated in 13 affected individuals across three generations, enabling presymptomatic diagnosis and guiding tailored follow-up (PMID:12203996). In a neonatal hyperinsulinemic cohort, heterozygous HNF4A mutations were found in 3/11 probands, confirming that the same alleles can underlie both early-life hypoglycemia and later-onset diabetes (PMID:18268044). These observations support strong autosomal dominant inheritance and multiple unrelated families with concordant segregation.

Functional studies of HNF4A P2 promoter variants (–192C>G, –169C>T, –136A>G) demonstrate impaired promoter activity in luciferase reporter assays, reducing transcriptional output by up to 40% compared with wild type (PMID:20546279). In vitro transactivation assays further show that coding polymorphisms Thr130Ile and Val255Met decrease HNF4A activity to 73–76% of wild type, correlating with altered insulin secretion and increased type 2 diabetes risk (PMID:15728204).

A promoter haplotype spanning P2 (–192C>G) has also been linked to later-onset diabetes and reduces HNF4A-driven transcription in vitro, supporting a haploinsufficiency mechanism (PMID:16731861). Concordant findings in mouse models and cellular assays illustrate that loss of one functional HNF4A allele diminishes β-cell gene networks, leading to progressive insulin secretory failure.

Despite occasional reports of reduced penetrance for specific variants (e.g., p.Arg114Trp) in large population cohorts, the preponderance of familial and functional data affirms a Strong clinical validity classification for HNF4A–MODY1. Comprehensive genotype-phenotype correlations guide precision diagnostics and sulfonylurea therapy, underscoring the utility of genetic testing for affected families.

Key take-home: Autosomal dominant HNF4A variants cause MODY1 through haploinsufficiency, and genetic diagnosis enables personalized management and family screening.

References

• Large Family With Maturity-Onset Diabetes of the Young and a Novel V121I Mutation in HNF4A. Human Mutation • 2002 • PMID:12203996
• Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes • 2008 • PMID:18268044
• HNF4A mutation: switch from hyperinsulinaemic hypoglycaemia to maturity-onset diabetes of the young, and incretin response. Diabetic Medicine • 2014 • PMID:20546279
• The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4α (HNF4A) gene associations with type 2 diabetes. J Clin Endocrinol Metab • 2005 • PMID:15728204
• A hepatocyte nuclear factor-4α gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes. Diabetes • 2006 • PMID:16731861

Evidence Based Scoring (AI generated)