{ "id": "ep9wrb17fh", "slug": "hnf1a", "title": "HNF1A", "updated": "2026-10-21", "topic_path": [ { "id": "life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/topics/life" }, { "id": "life.biology", "label": "Biological foundations", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology" }, { "id": "life.biology.genetics", "label": "Genetics and genomic reference", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics" }, { "id": "life.biology.genetics.gene_record_human", "label": "Human gene and locus records", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human" }, { "id": "life.biology.genetics.gene_record_human.transcription-factors-and-regulators", "label": "Transcription factors and regulators", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human.transcription-factors-and-regulators" }, { "id": "life.biology.genetics.gene_record_human.transcription-factors-and-regulators.homeobox-transcription-factors", "label": "Homeobox transcription factors", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human.transcription-factors-and-regulators.homeobox-transcription-factors" } ], "geo": [ { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.homeobox-transcription-factors", "label": "Non-geographic · Not dated: Homeobox transcription factors", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.homeobox-transcription-factors", "path": [ { "id": "geo.nongeo", "label": "Non-geographic", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo" }, { "id": "geo.nongeo.nodate", "label": "Non-geographic · Not dated", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate" }, { "id": "geo.nongeo.nodate.life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life" }, { "id": "geo.nongeo.nodate.life.biology", "label": "Biological foundations", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology" }, { "id": "geo.nongeo.nodate.life.biology.genetics", "label": "Genetics and genomic reference", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics" }, { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human", "label": "Human gene and locus records", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human" }, { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators", "label": "Transcription factors and regulators", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators" }, { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.homeobox-transcription-factors", "label": "Homeobox transcription factors", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.homeobox-transcription-factors" } ] } ], "excerpt": "HNF1A (TCF1, MODY3) is a human gene on chromosome 12q24.31 encoding the HNF-1α transcription factor that regulates liver-specific and beta-cell genes; pathogenic variants cause HNF1A-MODY, treatable with low-dose sulfonylureas, and somatic biallelic loss drives hepatocellular adenomas.", "snippet": "HNF1A (TCF1, MODY3) is a human gene on chromosome 12q24.31 encoding the HNF-1α transcription factor that regulates liver-specific and beta-cell genes; pathogenic variants cause HNF1A-MODY, treatable with low-dose sulfonylureas, and somatic biallelic loss drives hepatocellular adenomas.", "node": "life.biology.genetics.gene_record_human.transcription-factors-and-regulators.homeobox-transcription-factors", "markdown": "# HNF1A\n\n**HNF1A** (HNF1 homeobox A) is a human protein-coding gene on chromosome 12 that provides instructions for hepatocyte nuclear factor-1 alpha (HNF-1α), a transcription factor required for the expression of several liver-specific genes and for the development and function of insulin-producing pancreatic beta cells.[1](https://www.ncbi.nlm.nih.gov/gene/6927/) • [2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf) Inherited defects in one copy of the gene cause maturity-onset diabetes of the young type 3 (MODY3, also called HNF1A-MODY), one of the most common forms of monogenic diabetes, and acquired loss of function in liver cells contributes to benign liver tumors called hepatocellular adenomas.[1](https://www.ncbi.nlm.nih.gov/gene/6927/) • [2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf)\n\n| Key fact | Detail |\n|---|---|\n| Official name | HNF1 homeobox A (HGNC:11621), Gene ID 6927; aliases include TCF1, LFB1, HNF-1α, and MODY3[1](https://www.ncbi.nlm.nih.gov/gene/6927/) |\n| Location | Chromosome 12q24.31, 9 exons; GRCh38 coordinates NC_000012.12 (120978543..121002512)[1](https://www.ncbi.nlm.nih.gov/gene/6927/) |\n| Protein function | Transcription factor that works as a homodimer and binds the inverted palindrome 5'-GTTAATNATTAAC-3'[1](https://www.ncbi.nlm.nih.gov/gene/6927/) |\n| Main disease role | Causes MODY3 (HNF1A-MODY), estimated to account for roughly 40 to 70% of all MODY cases[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/) |\n| Penetrance | 63% of carriers develop diabetes before age 25, 79% before 35, and 96% before 55[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10107883/pdf/PEDI-23-1188.pdf) |\n| First-line treatment | Low-dose sulfonylurea, which lowers fasting glucose more than fourfold compared with metformin[5](https://wchh.onlinelibrary.wiley.com/doi/full/10.1002/pdi.2410) |\n| Liver tumors | HNF1A-mutated hepatocellular adenomas account for about 30 to 40% of hepatocellular adenomas[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf) |\n\n## Gene and protein\n\nThe gene sits at 12q24.31 on chromosome 12 and contains 9 exons; alternative splicing produces multiple transcript variants encoding different isoforms.[1](https://www.ncbi.nlm.nih.gov/gene/6927/) The RefSeq record lists three reviewed transcripts, including NM_000545.8 encoding isoform 2 and a longer variant NM_001306179.2 encoding isoform 1.[1](https://www.ncbi.nlm.nih.gov/gene/6927/) Expression is biased toward the kidney (RPKM 13.4) and duodenum (RPKM 9.8) among the tissues with the highest measured levels, and the protein is described as a widely expressed, tissue-specific transcription factor.[1](https://www.ncbi.nlm.nih.gov/gene/6927/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC8921476/)\n\n**Protein architecture.** HNF-1A is a multi-domain protein with an N-terminal dimerization domain (residues 1–33), a central [DNA-binding domain](https://www.edgepedia.org/dna-binding-domain), and a C-terminal transactivation domain of roughly 450 residues.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/) The dimerization domain is a 32-residue α-helical region that can fold and dimerize independently and mediates homodimerization or heterodimerization with the related protein HNF-1B; it also forms a heterotetramer with pterin-4 alpha-carbinolamine dehydratase 1 (PCBD1), which stabilizes the dimeric form.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/) The DNA-binding domain combines a Pit-Oct-Unc-specific (POU\\(_S\\)) domain and a homeodomain (POU\\(_H\\)), contains a nuclear-localization signal, and binds the inverted palindromic consensus sequence GTTAATNATTAAC.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/) Three isoforms (A, B, C) differ in the length of the C-terminal transactivation domain and are differentially expressed in fetal and adult tissues.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/)\n\n## Normal function\n\nHNF-1α binds specific regions of DNA and controls the activity of target genes, with particular importance in the pancreas and liver.[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf) Regulation of gene activity by HNF-1α is critical for the growth and development of pancreatic beta cells, which produce and secrete insulin, and the protein also controls genes involved in liver development.[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf) Within the liver, HNF1α controls the expression of many genes specific to that organ and plays a role in how glucose, lipids, and additional compounds are metabolized.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC8921476/) By controlling genes that regulate cell growth and survival, HNF-1α is thought to act as a tumor suppressor.[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf)\n\nIn the endocrine pancreas, HNF-1A regulates target genes involved in glucose regulation and metabolism, including those encoding the insulin receptor, HNF-4A, the glucose transporter GLUT2, and glucose-6-phosphatase; in a genome-location experiment using human pancreatic islets, HNF-1A occupied promoter regions of 106 islet genes.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/)\n\n## HNF1A-MODY (MODY3)\n\nPathogenic variants in HNF1A cause maturity-onset diabetes of the young type 3, a dominantly inherited form of diabetes with onset typically before 25 to 35 years of age and pancreatic beta-cell dysfunction.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/) HNF1A gene mutations cause the most common type of MODY, and early symptoms reflect high blood glucose: frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, weight loss, and recurrent skin infections.[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf) Mutations occur in one of the two copies of the gene in each cell and produce an altered HNF-1α protein unable to function normally; some changes prevent dimer formation, others prevent entry into the nucleus, and still others prevent binding to DNA.[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf)\n\n**Penetrance and age at onset.** Studies of HNF1A-MODY report high penetrance: 63% of mutation carriers develop diabetes before 25 years of age, 79% before 35, and 96% before 55.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10107883/pdf/PEDI-23-1188.pdf) Age at diagnosis depends partly on mutation position, with mutations in the terminal exons 8 to 10 leading to diagnosis on average 8 years later than mutations in exons 1 to 6.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10107883/pdf/PEDI-23-1188.pdf)\n\n**Penetrance depends on setting.** In clinically unselected cohorts, the penetrance of HNF1A pathogenic variants is substantially lower than in clinically referred probands: one study estimated 32% in the population, 49% in a health-system cohort, 86% in family members, and 98% in probands.[7](https://www.ncbi.nlm.nih.gov/research/pubtator3/publication/36257325) A genotype-first study of the [UK Biobank](https://www.edgepedia.org/uk-biobank) found HNF1A showed the highest penetrance among MODY genes examined, and identified parental history of diabetes and polygenic risk for type 2 diabetes as modifiers of penetrance (hazard ratios 2.54 and 1.52, respectively).[8](https://academic.oup.com/jcem/article/111/5/e1388/8307687) In that cohort, pathogenic variants in the HNF1A/HNF4A/[HNF1B](https://www.edgepedia.org/hnf1b) transcription-factor genes together had a population prevalence of 0.027% (1 in 3693).[8](https://academic.oup.com/jcem/article/111/5/e1388/8307687) A separate analysis of 17 proposed MODY genes classified HNF1A among the 6 genes statistically consistent with being highly penetrant.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC9659663/)\n\n## Treatment\n\nIndividuals with MODY due to HNF1A mutations can be treated with low-dose sulfonylurea therapy but may ultimately require insulin.[10](https://diabetesjournals.org/care/article/49/Supplement_1/S183/163934/) Low-dose sulfonylurea is the first-line treatment and results in a greater than 4-fold reduction in fasting glucose compared with metformin.[5](https://wchh.onlinelibrary.wiley.com/doi/full/10.1002/pdi.2410) For people with HNF1A mutations, adding a DPP-4 inhibitor to the sulfonylurea may help improve glycemic variability and attainment of glycemic goals.[10](https://diabetesjournals.org/care/article/49/Supplement_1/S183/163934/) Because chronic complications develop in a large proportion of patients with HNF1A-MODY, optimal disease control should be pursued early after onset.[11](https://ptdiab.pl/images/docs/zalecenia/2021-Guidelines-on-the-management-of-patients-with-diabetes.pdf) Studies have shown good maintenance on sulfonylurea therapy and lower rates of diabetes-related complications in treated patients.[12](https://www.endotext.org/wp-content/uploads/pdfs/diagnosis-and-clinical-management-of-monogenic-diabetes.pdf)\n\nA distinctive feature of HNF1A biology affects the kidney: individuals with HNF1A mutations display drastically decreased expression of SGLT2, reducing glucose reabsorption in the proximal tubule and lowering the renal glucose threshold, so glycosuria can appear at near-normal glucose levels.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC4890265/)\n\n## Hepatic adenomas\n\nRarely, individuals with HNF1A-MODY develop one or more benign liver tumors called hepatocellular adenomas; in these individuals a second, non-inherited (somatic) mutation occurs in the other copy of HNF1A in liver cells.[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf) Hepatocellular adenomas also occur in people without HNF1A-MODY through somatic mutations in both copies of the gene; HNF1A-mutated adenomas (H-HCA) account for about 30 to 40% of this tumor type, occur more frequently in women than in men, and most affected individuals develop a single tumor.[2](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf) The NCBI gene summary likewise notes that defects in HNF1A can result in the appearance of hepatic adenomas.[1](https://www.ncbi.nlm.nih.gov/gene/6927/)\n\n## Variant interpretation and type 2 diabetes risk\n\nAccording to ClinVar as reviewed in 2022, 418 variants of HNF1A had been reported, of which 131 were recognized as pathogenic or likely pathogenic; diabetes-associated missense mutations occur at the highest rates in the DNA-binding domain, at an intermediate rate in the dimerization domain, and at a low rate in the transactivation domain.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/) Functional assays inform classification: the ClinGen Monogenic Diabetes Expert Panel notes that MODY-causal HNF1A variants impair transactivation activity more severely (below 40% of wild type) than type 2 diabetes risk variants (40 to 75% of wild type).[14](https://www.clinicalgenome.org/site/assets/files/7039/clingen_diabetes_acmg_specifications_v1.pdf) Structural and biophysical characterization of variant proteins, such as the unstable P112L and the DNA-binding-defective R263C, supports mechanistic explanations of disease causality and variant classification.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/)\n\nHNF1A variation also contributes to common diabetes. The p.E508K variant, located in the transactivation domain, preserves DNA binding but shows compromised transactivation on the promoters of [SLC2A2](https://www.edgepedia.org/slc2a2) and [HNF4A](https://www.edgepedia.org/hnf4a) in beta cells, and rare HNF1A variants act as risk factors for type 2 diabetes in the general population.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC4890265/) Genome-wide association studies have additionally linked HNF1A polymorphisms to [C-reactive protein](https://www.edgepedia.org/c-reactive-protein) levels.[15](https://www.ncbi.nlm.nih.gov/gene/006927)\n\n## References\n\n1. [HNF1A HNF1 homeobox A [Homo sapiens (human)] – Gene – NCBI, Gene ID 6927](https://www.ncbi.nlm.nih.gov/gene/6927/)\n2. [HNF1A gene, MedlinePlus Genetics (NIH)](https://medlineplus.gov/download/genetics/gene/hnf1a.pdf)\n3. [Kind L, et al. (2022). Structural and biophysical characterization of transcription factor HNF-1A as a tool to study MODY3 diabetes variants. J Biol Chem.](https://pmc.ncbi.nlm.nih.gov/articles/PMC8988010/)\n4. [ISPAD Clinical Practice Consensus Guidelines 2022: diagnosis and management of monogenic diabetes in children and adolescents, Pediatric Diabetes](https://pmc.ncbi.nlm.nih.gov/articles/PMC10107883/pdf/PEDI-23-1188.pdf)\n5. [Colclough K, et al. (2022). An update on the diagnosis and management of monogenic diabetes, Practical Diabetes](https://wchh.onlinelibrary.wiley.com/doi/full/10.1002/pdi.2410)\n6. [HNF1A: From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8921476/)\n7. [Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts, PMC (abstract record)](https://www.ncbi.nlm.nih.gov/research/pubtator3/publication/36257325)\n8. [Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY, J Clin Endocrinol Metab](https://academic.oup.com/jcem/article/111/5/e1388/8307687)\n9. [Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9659663/)\n10. [Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2026, Diabetes Care](https://diabetesjournals.org/care/article/49/Supplement_1/S183/163934/)\n11. [Clinical Diabetology 2021, Vol. 10, No. 1: Guidelines on the management of patients with diabetes](https://ptdiab.pl/images/docs/zalecenia/2021-Guidelines-on-the-management-of-patients-with-diabetes.pdf)\n12. [Diagnosis and Clinical Management of Monogenic Diabetes, Endotext](https://www.endotext.org/wp-content/uploads/pdfs/diagnosis-and-clinical-management-of-monogenic-diabetes.pdf)\n13. [Monogenic Diabetes: What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4890265/)\n14. [ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines, Version 1](https://www.clinicalgenome.org/site/assets/files/7039/clingen_diabetes_acmg_specifications_v1.pdf)\n15. [HNF1A gene record with GWAS Catalog links (C-reactive protein loci), NCBI](https://www.ncbi.nlm.nih.gov/gene/006927)\n\n---\n*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Human gene and locus records › Transcription factors and regulators › Homeobox transcription factors*\n\n*Initially written Oct 21, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/hnf1a", "markdown_url": "https://www.edgepedia.org/hnf1a.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"HNF1A\", Edgepedia (EdgeChat), https://www.edgepedia.org/hnf1a. Edgepedia Community License 1.0.", "credit_md": "\"[HNF1A](https://www.edgepedia.org/hnf1a)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/hnf1a](https://www.edgepedia.org/hnf1a). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"HNF1A\", Edgepedia (EdgeChat), https://www.edgepedia.org/hnf1a. Edgepedia Community License 1.0.", "speakable": "HNF1A is a human gene on chromosome 12q24.31 encoding the HNF-1α transcription factor that regulates liver-specific and beta-cell genes; pathogenic variants cause HNF1A-MODY, treatable with low-dose sulfonylureas, and somatic biallelic loss drives hepatocellular adenomas." }