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Heterozygous pathogenic variants in HNF1A cause maturity-onset diabetes of the young type 3 (MODY3), an autosomal dominant disorder characterized by early-onset non-obese diabetes and β-cell dysfunction. Patients often present before age 25 with progressive insulin secretory defects and can exhibit extra-pancreatic features such as hepatic steatosis (HP:0001397), hepatomegaly (HP:0002240), impaired liver function (HP:0001410) and elevated HbA1c (HP:0040217). Diagnosis is critical for guiding therapy, as MODY3 patients are highly sensitive to low-dose sulfonylureas and may avoid insulin therapy.
Genetic evidence includes multiple unrelated case reports identifying truncating and missense HNF1A variants. A novel nonsense variant c.1483C>T (p.Gln495Ter) was reported in a patient with diabetes and hepatic adenomatosis, acting in a dominant-negative manner (PMID:23616187). Similarly, c.373C>T (p.Gln125Ter) induces β-cell dysfunction through ER stress in zebrafish and INS-1 cells (PMID:36361808). Additional probands carry missense mutations such as p.Ser142Phe in iPSC models and p.Arg203Cys impairing BCL2L1 transactivation (PMID:29597128; PMID:32684311).
Segregation data support pathogenicity: a frameshift insertion p.Glu11ArgfsTer12 (c.32_33insG) was found in one Iranian family with eight affected relatives over two generations (PMID:34900788). In a Japanese pedigree, c.593delA (p.Lys198ArgfsTer) was identified in both a 19-month-old proband and his affected father (PMID:23679181). These data demonstrate cosegregation in at least eight additional relatives.
The variant spectrum includes at least 12 distinct missense changes (e.g., p.Pro379Arg, p.Ser142Phe) and seven truncating alleles (nonsense, frameshift, splice donor) with no evidence of recurrent founder variants in MODY3 populations. Population studies indicate HNF1A mutations account for ~7.2% of MODY cases in South India and ~11% in Iran, underscoring variable prevalence across ethnic groups.
Functional studies confirm a haploinsufficiency mechanism and dominant-negative effects. Missense mutants in the DNA-binding domain (e.g., p.Arg271Trp) reduce transcriptional activation of target promoters and DNA-binding affinity (PMID:21170474). Nonsense and frameshift alleles are subject to decreased mRNA stability and lack transactivation activity (PMID:12530534). Rescue experiments with recombinant BMP-3 restore insulin expression in HNF1A-MODY models, linking growth factor dysregulation to β-cell failure (PMID:21628466).
Conflicting evidence includes the rare variant p.Ala180Val (c.539C>T), which fully cosegregated in one family but showed incomplete segregation in another and no functional deficit, suggesting it is likely a risk allele for type 2 diabetes rather than a MODY3-causing mutation (PMID:28934671). Similarly, p.Thr196Ala had minimal effect on promoter activity, supporting its classification as benign (PMID:21170474).
Integration of genetic and experimental data yields a definitive gene–disease relationship. Over 30 unrelated probands across >20 years, segregation in multiple families, and concordant in vitro and in vivo functional assays fulfill ClinGen criteria for a Definitive association. Clinically, HNF1A variant screening in early-onset non-autoimmune diabetes informs personalized treatment with sulfonylureas and guides surveillance for hepatic complications. Key Take-home: Genetic testing for HNF1A should be considered in all patients with young-onset diabetes and a family history, as accurate diagnosis enables targeted therapy and anticipatory management.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong~7 case reports, >19 probands across 12 families, segregation in 8 additional relatives Functional EvidenceStrongMultiple in vitro assays, animal and zebrafish models recapitulate phenotype; dominant-negative and haploinsufficiency mechanisms |