Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance. To date, 14 distinct MODY subtypes have been identified, among which HNF1A-MODY, caused by HNF1A gene mutations, represents one of the most prevalent subtypes, accounting for 30-70% of all MODY cases (1). However, recent study indicates that within the Chinese MODY population, the proportion of HNF1A-MODY cases is 16.03% (2). The HNF1A gene encodes hepatocyte nuclear factor 1α (HNF1α), a transcriptional regulator that activates insulin gene expression in pancreatic β-cells. Structurally, HNF1α consists of three functional domains (3): an N-terminal dimerization domain (residues 1-32), a DNA-binding domain (residues 91-281), and a C-terminal transactivation domain (residues 282-631). HNF1A-MODY is characterized by defective insulin secretion and progressive hyperglycemia, with a high prevalence of microvascular complications (4). The clinical phenotypes of HNF1A-MODY patients exhibit considerable heterogeneity and overlap with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) (5), often leading to misdiagnosis. Therefore, early and accurate genetic diagnosis followed by precision therapy is essential for improving clinical management and long-term outcomes.

The marked heterogeneity in the clinical manifestations of HNF1A-MODY may be attributed to the variability in mutation loci (6). Previous studies have indicated that both the type and location of HNF1A mutations influence the age at diagnosis (7, 8), response to sulfonylurea therapy (9), and risk of diabetic complications (10). Additionally, genetic modifiers and exposure to intrauterine hyperglycemia may contribute to the variability in HNF1A-MODY diagnosis age (11, 12). However, the current researches were mainly based on data from Caucasian and other non-Chinese Asian populations, while systematic analyses of Chinese HNF1A-MODY patients remain scarce. Additionally, the impact of domain-specific HNF1A mutations on metabolic indicators such as pancreatic function and lipids has not been thoroughly investigated.

This study analyzed patients with HNF1A-MODY admitted to Qilu Hospital of Shandong University, along with reported Chinese cases from published literature, to investigate the genotype-phenotype correlations associated with domain-specific HNF1A mutations. This study aims to provide a basis for developing personalized management strategies by investigating the association between specific mutation sites and patients’ clinical manifestations, thereby improving the prognosis of HNF1A mutation carriers.

This study analyzed the clinical characteristics of Chinese patients with HNF1A-MODY and revealed associations between mutations in different functional domains and clinical phenotypes. This multicenter cross-sectional analysis of Chinese population revealed that patients with DNA-binding domain variants exhibited a significantly younger age of onset, as well as lower FCP, LDL-C, TC levels, and higher HDL-C levels compared to patients with dimerization or transactivation domain mutations. Short-term follow-up revealed that HNF1A-MODY patients with poor glycemic control might had higher baseline BMI and LDL-C levels. ANCOVA indicated that DNA-binding domain mutations were independently associated with lower FCP, LDL-C and higher HDL-C levels.

HNF1A-MODY is a monogenic form of diabetes caused by pathogenic variants in the HNF1A gene. The HNF1A gene, located on chromosome 12q24 (14), encodes the hepatocyte nuclear factor 1 alpha (HNF1α) protein, which is predominantly expressed in the liver, pancreas, kidney, and gastrointestinal tract (15). HNF1α plays a critical role in regulating genes involved in insulin secretion, glucose metabolism, and lipid homeostasis. To date, approximately 500 HNF1A variants have been reported in association with MODY phenotypes (16). The HNF1A gene exhibits high polymorphism, with the highest mutation rate in exons 2 and 4 (17, 18). A retrospective study of patients with HNF1A-MODY reported 492 different mutations (10), and missense mutations (227, 46.1%) and frameshift mutations (198, 40.2%) were the most common mutations. Whereas in the Qilu Hospital cohort, 22 distinct HNF1A gene variants were identified, eight of which were novel, mainly located in exons 2 and 4, with missense and frameshift mutations being the main types, consistent with the previous findings.

The HNF1α protein comprises three functional domains: the dimerization domain mediates homodimerization or heterodimerization with homologous proteins such as HNF1β (19), which is fundamental for DNA-binding and transcriptional regulation, and aberrant assembly of the dimeric complex leads to impaired target gene binding and reduced transactivation activity. The DNA-binding domain consists of a POU-specific domain (POUS) and a POU homeodomain (POUH). POUS maintains protein stability, and POUH is critical for initiating protein-DNA interactions at promoter regions of target genes (20). The nuclear localization of HNF1α depends on specific nuclear localization signals, with residues 158-171, 197-205, and 271–282 are considered to be nuclear localization regions (21), mutations affecting these regions may lead to loss of transcriptional regulation. The transactivation domain recruits coactivators such as p300/CBP to activate the transcription of glucose metabolism-related genes (22). In our study, the number of cases in the dimerization domain group was relatively small, which may be attributed to the overall low frequency of mutations in this domain across populations. A retrospective study on HNF1A-MODY patients reported that (10) in non-Asian populations, mutation rates were approximately 7.8% in the dimerization domain, 29.2% in the DNA-binding domain, and 47.5% in the transactivation domain. Among Asian populations, the corresponding proportions were 3.8%, 48.8%, and 47.5%, with no significant difference in domain-specific mutation distribution between the two groups. Of the 432 patients with coding−region mutations for whom mutation sites were reported, only 15 occurred in the dimerization domain. In our Qilu Hospital cohort, mutations were observed in 8.7% of cases within the dimerization domain, 39.1% within the DNA-binding domain, and 52.2% within the transactivation domain, consistent with previous reports.

Previous researches demonstrated that the DNA-binding domain of HNF1α plays a more critical role in regulating blood glucose, and the dimerization domain plays the second most important role (17), indicating a possible genotype-phenotype correlation in HNF1A-MODY. To explore the association between genotype and clinical phenotypes in Chinese HNF1A-MODY patients, our study enrolled a total of 136 patients with from our cohort, together with previously reported cases from China identified through a review of published literature. Combined analysis with literature-sourced HNF1A-MODY cases revealed that patients with the dimerization and DNA-binding domain mutations presented a younger age of onset and lower FCP levels. Besides, patients with DNA-binding domain mutation exhibited significantly lower 2hPCP levels than those with transactivation domain mutation, suggesting that DNA-binding domain mutation cause more severe insulin secretion defects. This clinical difference indicates that mutations in the transactivation domain may lead to a milder diabetic phenotype. The impact of mutations varies by domain: mutations in the dimerization or DNA-binding domain impair DNA-binding capacity (23) and may cause more severe insulin secretion defects, resulting in a younger age of onset and lower C-peptide levels. The transactivation domain demonstrates greater tolerance to mutations that result in small changes in HNF1α protein structure than the dimerization or DNA-binding domain (24, 25). ANCOVA further confirmed that dimerization domain and DNA-binding domain mutation were independently associated with lower FCP levels. A comparison of the activity of the mutant and wild-type proteins revealed that mutations in the transactivation domain disrupted transcriptional activity less than mutations in the DNA-binding domain, as it primarily affected coactivator recruitment rather than DNA-binding affinity (26). This study is the first to reveal in a Chinese population that dimerization domain and DNA-binding domain mutations in HNF1A-MODY are associated with poorer pancreatic islet function. This finding provides a basis for assessing patient prognosis and formulating treatment strategies.

Regarding treatment, sulfonylureas are widely acknowledged as the first-line therapy for HNF1A-MODY (23); however, a notable proportion of patients in our study were treated with insulin. Real-world data and reviews indicate that insulin use is indeed common among genetically confirmed HNF1A-MODY patients. The real-world study (27) revealed that the insulin usage rate within one year after diabetes diagnosis was 52% (35% insulin monotherapy, 17% insulin combined with oral hypoglycemic agents). Even after genetic diagnosis of HNF1A-MODY, insulin usage remained at 42% (25% insulin alone, 17% insulin combined with oral agents). A review on the clinical characteristics of HNF1A-MODY patients (10) reported that insulin usage was 16.7% in those with dimerization domain mutations, 33.8% in DNA-binding domain, and 33.2% in transactivation domain. In our study, after excluding patients with variants of uncertain significance, the corresponding insulin usage rates for these domains were 33.3%, 35.3%, and 45.28%, respectively. The widespread use of insulin in HNF1A-MODY is likely attributable to diagnostic delay or treatment patterns, rather than true insulin dependence. Therefore, inferring domain-specific treatment responses based on current insulin use should be approached with caution. Instead, prospective therapeutic trials with sulfonylurea should be systematically conducted following genetic diagnosis.

In addition, our data showed that patients with DNA-binding domain mutations had lower LDL-C and TC levels, but higher HDL-C levels. HNF1α is involved in bile acid and plasma cholesterol metabolism (28). Prior studies have shown that liver-specific knockdown of HNF1α reduces LDL-C levels in normolipidemic mice (29), though similar effects have not been observed in humans. Our results suggest a potential domain-specific correlation with lipid regulation, but the precise mechanisms require further investigation.

This study also characterized the clinical profile and short-term treatment patterns associated with different glycemic control statuses. After a 2-year follow-up of the patients from Qilu Hospital, the majority achieved target glycemic levels; however, some developed new-onset diabetic peripheral neuropathy or diabetic retinopathy within this observation period. Notably, poor glycemic control was associated with higher baseline levels of BMI and blood lipids. These findings appear to support the association between chronic hyperglycemia and microvascular complications in this cohort, and may also underscore the potential role of weight and lipid management in short-term metabolic outcomes. Regarding pharmacotherapy, patients with good glycemic control were more likely to use sulfonylurea monotherapy, whereas those with poor control required insulin-based combination therapy. This observation aligns with the characteristic hypersensitivity to sulfonylureas in HNF1A-MODY patients, for whom these agents are considered first-line therapy (23). Although recent case reports identified novel HNF1A variants exhibiting resistance to sulfonylureas and other glucose-lowering drugs (9, 30), such variants were not identified in our cohort. Given that HNF1A-MODY patients exhibit progressive β-cell dysfunction and remain at high risk for both microvascular and macrovascular complications (31–33), early diagnosis coupled with stringent glycemic control is crucial for reducing the prevalence of late-diabetic complications (34, 35). However, given the relatively short follow-up period, longer-term studies will be needed to clarify prognosis and the durability of treatment effects.

This study has several limitations. First, the relatively small sample size, particularly the low number of cases in the dimerization domain group may affect statistical power and limit the generalizability of the findings. Second, the relatively short follow-up period is insufficient for comprehensively assessing long-term complication risks and does not provide strong support for long-term prognosis. To evaluate the impact on long-term outcomes, we are conducting ongoing follow-up of the patient cohort. Third, literature-derived cases exhibited variability in diagnostic criteria and laboratory methods, along with incomplete clinical variables, which may introduce selection and measurement biases and increase clinical data heterogeneity. Fourth, while we performed a sensitivity analysis excluding patients with early insulin dependence, the overall high prevalence of insulin therapy in our combined cohort may still reflect regional diagnostic delays or historical treatment patterns rather than intrinsic sulfonylurea unresponsiveness. This could introduce residual confounding when assessing metabolic phenotypes. Moreover, a subset of patients in the adolescent type 2 diabetes control group did not undergo genetic testing, which may to some extent affect the specificity of intergroup comparisons. Furthermore, the absence of functional studies on the identified variants restricts mechanistic interpretation of domain−specific mutation effects. Future multicenter studies with larger cohorts and longer follow-up durations, combined with functional characterization of mutant proteins, are needed to better elucidate the predictive value of different variant types for drug response and complication risks.

In conclusion, this study demonstrated domain-specific effects of HNF1A mutations. Pancreatic islet function was significantly associated with the location of the mutation. Mutations in the dimerization domain and DNA-binding domains were associated with an earlier age of onset and more severe insulin secretion defects. Regarding lipid metabolism, our analyses indicated an observational association between DNA-binding domain mutations and a distinct lipid profile characterized by lower LDL-C and higher HDL-C levels. This study summarized the association between clinical phenotypes and genotypes in patients with HNF1A-MODY, revealed the correlation between HNF1A mutation regions and pancreatic islet function as well as blood lipid levels, thereby providing a theoretical foundation for predicting pancreatic islet function prognosis through gene sequencing and guiding individualized treatment options.