HNF4A – Maturity-onset Diabetes of the Young Type 1

Hepatocyte nuclear factor 4 alpha (HNF4A) is a nuclear transcription factor critical for pancreatic β-cell differentiation and function. Heterozygous loss-of-function variants in HNF4A cause maturity-onset diabetes of the young type 1 (MODY1) with autosomal dominant inheritance. Clinical features include elevated fasting glucose and hemoglobin A1c, and sensitivity to sulfonylureas supports a β-cell defect (PMID:23652628).

Genetic evidence for HNF4A–MODY1 includes linkage of a P2 promoter haplotype (–192C>G) with diabetes in two Norwegian families (LOD 3.1 and 0.8) and in Danish pedigrees (PMID:16731861). Two novel coding variants, c.824A>G (p.Asn275Ser) and c.692_695delAGGA (p.Lys231ThrfsTer5), co-segregated in two Japanese families with early-onset diabetes and elevated HbA1c (PMID:23652628). Recent exome sequencing identified three missense variants (p.Ile159Thr, p.Trp179Cys, p.Asp260Asn) in three unrelated MODY1 pedigrees of Chinese ancestry with full co-segregation (PMID:37711893).

Functional assays demonstrate that the missense variant c.824A>G (p.Asn275Ser) reduces HNF4A transactivation activity in luciferase reporter assays by >50% in HepG2 cells, consistent with haploinsufficiency (PMID:23652628). Promoter studies revealed that P2 promoter mutations including –192C>G, –169C>T, and –136A>G significantly impair promoter-driven luciferase expression, confirming a regulatory mechanism (PMID:20546279).

In silico modeling and biochemical studies of the novel D248Y variant (c.742G>T, p.Asp248Tyr) show disrupted heterodimer formation and reduced INS promoter activation across HNF4A isoforms, indicating dominant-negative effects (PMID:38745825). Similarly, the R258H mutation alters surface electrostatics at the dimer interface and decreases transactivation in luciferase assays, implicating impaired protein stability in disease pathogenesis (PMID:30325586).

No studies refute the HNF4A–MODY1 association. The consistent co-segregation of heterozygous variants in multiple families, along with concordant functional impairments across independent cellular and in silico models, supports a strong gene–disease relationship. Clinically, accurate genetic diagnosis of HNF4A-MODY1 guides optimal management, including early initiation of sulfonylureas and avoidance of insulin in many patients.

Key take-home: HNF4A heterozygous variants cause autosomal dominant MODY1 through haploinsufficiency and dominant-negative mechanisms, and precise molecular diagnosis enables targeted therapy.

References

• Diabetes • 2006 • A hepatocyte nuclear factor-4 alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes PMID:16731861
• Hormone research in paediatrics • 2013 • Detection and characterization of two novel mutations in the HNF4A gene in maturity-onset diabetes of the young type 1 in two Japanese families PMID:23652628
• Diabetic medicine : a journal of the British Diabetic Association • 2010 • Novel monogenic diabetes mutations in the P2 promoter of the HNF4A gene are associated with impaired function in vitro PMID:20546279
• Frontiers in endocrinology • 2023 • Identification and precision therapy for three maturity-onset diabetes of the young (MODY) families caused by mutations in the HNF4A gene PMID:37711893
• Journal of diabetes investigation • 2019 • In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4α identified in maturity-onset diabetes of the young typ PMID:30325586
• Journal of the Endocrine Society • 2024 • Functional Analysis of a Novel HNF4A Variant Identified in a Patient With MODY1 PMID:38745825

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