Figure 2 - available via license: CC BY-NC-ND
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25 HNF1α protein interaction partners (STRING database). Nodes -each node represents all the splice isoforms produced by a single, protein-coding gene locus. Empty nodes represent proteins of unknown 3D structure and filled nodes represent proteins with known or predicted 3D structure. This interaction network is not focused on any human tissue. Lines -every line color represents different manner of the protein interaction. Light blue -from curated databases. Purple -experimentally determined. Green -predicted interaction based on gene neighborhood. Red -predicted interaction based on gene fusion. Dark blue -predicted interaction based on gene co-occurrence (i.e. phylogenetic distribution of protein orthologs in a human). Yellow -automated textmining of the scientific literature. Black -co-expression. White -protein homology. Modified by (Szklarczyk et al. 2017).
Source publication
MODY (Maturity Onset Diabetes of the Young) is a type of diabetes resulting from a pathogenic effect of gene mutations. Up to date, 13 MODY genes are known. Gene HNF1A is one of the most common causes of MODY diabetes (HNF1A-MODY; MODY3). This gene is polymorphic and more than 1200 pathogenic and non-pathogenic HNF1A variants were described in its...
Context in source publication
Context 1
... online protein-protein interaction (PPI) databases present many more HNF1α interaction partners and each differs based on information sources they use. STRING database present 26 HNF1α interaction partners ( Figure 2). This database groups known and predicted PPI including direct (physical) and indirect (functional) associations. ...
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Citations
... Using integrative transcriptomic and epigenomic analysis, Weng et al. showed that HNF1A expression was reduced in β-cells from T2D donors [44]. Heterozygous mutations in HNF1A are sufficient to cause the most frequent form of the maturity onset diabetes of the young (MODY) [53]. Because of these findings, along with reports stating that common variants at the HNF1A locus have been associated with T2D [54], the authors propose a causal role for HNF1A regarding β-cell heterogeneity in T2D pathogenesis. ...
The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.
... This gene is polymorphic and more than 1200 pathogenic and non-pathogenic https://epjournals.com/journals/EJM HNF1A variants were described in its UTRs, exons and intron [28]. It often manifests in adolescents or young adults, usually before age 30. ...
... MODY was defined as monogenic form of diabetes with an autosomal dominant inheritance that occurs before the age of 25 years due to a defect in the function of β cells. The subtypes of MODY traditionally include mutations of the genes ABCC8, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, NEUROD1, PDX1, BLK, KLF11 and PAX4 [28]. Genes implicated in MODY are crucial in β-cell development, function and regulation, as well as glucose sensing, and include the insulin gene 18 The causative mutations are inherited in an autosomal dominant pattern. ...
Platelet dysfunction in diabetes mellitus is a multifaceted issue with significant implications for vascular health. The interplay of hyperglycemia, oxidative stress, abnormal lipid profiles, endothelial dysfunction, inflammation, and medications can collectively disrupt platelet function. This dysfunction not only raises the risk of thrombosis and cardiovascular complications but also underscores the importance of comprehensive diabetes management. By controlling blood sugar levels, addressing associated risk factors, and working closely with healthcare providers, individuals with diabetes can mitigate the adverse effects of platelet dysfunction and reduce the likelihood of cardiovascular events.
... Hiện người ta đã phát hiện hơn 400 biến thể HNF1a trong gia đình MODY, có trong các cơ quan có nguồn gốc nội bì như gan, thận, tụy, ruột, dạ dày, lách, tuyến ức, tinh hoàn, tế bào sừng và tế bào hắc tố trên da người nhưng HNF1a dường như phổ biến trong gan và tụy [7]. HNF1a có liên kết với không dưới 222 gen mục tiêu ở gan và 106 gen mục tiêu trong đảo tuỵ người [8]. HNF1a là một yếu tố phiên mã cần thiết cho quá trình tiết Insulin bình thường và duy trì số lượng tế bào beta trong tuyến tuỵ. ...
Đái tháo đường khởi phát ở tuổi trưởng thành của người trẻ (Đái tháo đường thể MODY) là một dạng trong bệnh đái tháo đường đơn gen được đặc trưng bởi: Tuổi khởi phát trước 25 tuổi, không có tự kháng thể kháng tế bào beta đảo tụy, chức năng tế bào beta tụy được bảo tồn và gây ra do dột biến trên nhiễm sắc thể thường. HNF1a- MODY (MODY3) là dạng phổ biến nhất trong MODY và gây ra do đột biến di hợp tử gen HNF1a. Chúng tôi báo cáo một trường hợp lâm sàng bệnh nhân nữ 18 tuổi đã được chẩn đoán xác định MODY3 bằng xét nghiệm gen. Ngay tại thời điểm chẩn đoán, bệnh nhân đã có các biến chứng về mắt nặng nề bao gồm bong võng mạc cả hai bên. Các biện pháp điều trị bằng insulin, sulfonylurea, gliptin cũng như các can thiệp về mắt đối với bệnh nhân đã mang lại hiệu quả rõ rệt.
... We used chromVAR 30 to identify TF motifs that are enriched or depleted along the T2D trajectory; these results were then cross-referenced to the scRNA-RePACT results to predict causal TFs (Fig. 5d, e). Notable downregulated TFs include HNF1A/B and RFX6, which have known diabetes association and/or play important roles in β-cell function [31][32][33][34][35] . Notable up-regulated TFs include NEUROD1, nuclear transcription factor (NFYs), and TP53, etc. (Fig. 5d, e), which may reflect the β-cell death and dedifferentiation reported in diabetes 36,37 . ...
... In humans, heterozygous mutations in HNF1A are sufficient to cause the most frequent form of maturity onset diabetes of the young (MODY3) 31 . Since most of the HNF1A mutations in MODY3 are simple loss-of-function mutations, it has been proposed that the β-cell is particularly vulnerable to decreased HNF1A gene dosage 49,50 . ...
Broad heterogeneity in pancreatic β-cell function and morphology has been widely reported. However, determining which components of this cellular heterogeneity serve a diabetes-relevant function remains challenging. Here, we integrate single-cell transcriptome, single-nuclei chromatin accessibility, and cell-type specific 3D genome profiles from human islets and identify Type II Diabetes (T2D)-associated β-cell heterogeneity at both transcriptomic and epigenomic levels. We develop a computational method to explicitly dissect the intra-donor and inter-donor heterogeneity between single β-cells, which reflect distinct mechanisms of T2D pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between β-cells from the same donors; HNF1A expression is also reduced in β-cells from T2D donors. Interestingly, HNF1A activity in single β-cells is significantly associated with lower Na+ currents and we nominate a HNF1A target, FXYD2, as the primary mitigator. Our study demonstrates the value of investigating disease-associated single-cell heterogeneity and provides new insights into the pathogenesis of T2D.
... 4 The gene HNF1A is composed of ten exons, encoding a transcription factor of 631-amino acid protein that contains three functional domains: an N-terminal dimerization domain , a homeobox DNA binding domain (82-281) and a transactivation domain (282-631). 5 HNF1a plays a critical role in controlling the expression of many liver-specific genes. 6 It is essential for the differentiation of hepatocytes and the maintenance of normal liver function. ...
... [16][17][18] To date, over 1000 variants spanning from the promoter to the 3 0 UTR region have been identified in the HNF1A gene. 5 Although certain mutations have been employed to access the impact of HNF1A in other tissues, 19,20 there is currently a paucity of models carrying functional mutations to investigate the role of HNF1A in the liver. ...
... HNF1A is the genetic cause of several metabolic disorders, such as MODY3, Hyperinsulinaemic hypoglycaemia (HH), hepatocellular adenoma and HCC. 5,[35][36][37] Although most studies about HNF1A have focused on the disorders of glucose metabolism, the hepatic lipid metabolism of patients with HNF1A variants does not draw sufficient attention. MODY3 is the most prevalent disorder caused by mutations in the HNF1A gene. ...
Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1Amut/-) and found that the mutant mice developed liver steatosis spontaneously under the normal chow diet. Transcriptome analysis showed significant upregulation of Cfd and other genes related to innate immune response in the liver of hHNF1Amut/- mice. The changes in lipid metabolism and complement pathways were also confirmed by proteomics. We demonstrated that HNF1α inhibited CFD expression in hepatocytes, and the P291fsinsC mutant could reverse this inhibitory effect. Furthermore, the suppression of CFD with specific inhibitor or siRNAs reduced triglyceride levels in hepatocytes, suggesting that CFD regulated hepatocyte lipid deposition. Our results demonstrate that the HNF1α P291fsinsC mutant promotes hepatic steatosis and inflammation by upregulating CFD expression, and targeting CFD may delay the progression of nonalcoholic fatty liver disease.
... HNF1A encodes a transcription factor (TF) that binds to promoters of a variety of genes expressed predominantly in the liver and also in pancreatic islet cells 21 ; an association between polymorphism rs1169288 of HNF1A and the risk of T2DM has been identified in a Chinese population 22 . Also, mutations found in HNF1A could cause maturity-onset diabetes in youth type 3, primarily through impaired insulin secretion 23 . In addition, rs1169288 of HNF1A was found to be linked to hypertriglyceridemia 24 and linked to hypertension 25 ; all of these results suggest that the HNF1A gene might be involved in the etiology of PCOS 18 . ...
Polycystic ovary syndrome (PCOS) is one of the most common causes of female infertility. Clinical features caused by high levels of androgens, oligomenorrhea, and polycystic ovarian morphology are necessary for diagnosis. This study aims to find a relationship between the genetic polymorphism of HNF1A and the risk of Polycystic Ovary Syndrome in a Sample of Iraqi Women. The study includes one hundred subjects of Iraqi women in Baghdad (15-35 years); patients were divided into three groups. The first group included Patients treated with metformin, the second group included Patients without metformin, and the third group included healthy. DNA was extracted, then the Genotyping polymorphism (rs1169288) of the HNF1A gene was done by RT-PCR. The AA genotype showed a higher frequency in control (p=0.001), while the CC genotype showed a higher frequency in the patients (p= 0.0001). Keywords: Polycystic ovary syndrome (PCOS), genetic polymorphism, HNF1A protein, Glucose and lipid profile.
... Opisano funkcjonalne formy HNF1A i HNF4A, które powstają w wyniku alternatywnego splicingu i różnic w poliadenylacji, a ich ekspresja jest specyficzna tkankowo. Np. w trzustce dominuje izoforma HNF1A(B) [16,26,27]. Mutacje utraty funkcji genów HNF1A, HNF4A i HNF1B skutkują zaburzeniami funkcji komórek β, prowadzącymi do rozwoju niektórych typów cukrzycy MODY oraz nieprawidłowościami rozwojowymi wątroby i nerek [28]. ...
... Jest to najczęstszy podtyp MODY i jednocześnie drugi co do częstości wśród dzieci [1,28]. W Polsce częstość HNF1A--MODY stanowi 15% wszystkich podtypów MODY, podczas gdy w krajach skandynawskich i w Wielkiej Brytanii odpowiada za ponad 50% wszystkich zachorowań na ten podtyp cukrzycy [27]. ...
... W badaniach przeprowadzonych z udziałem ponad 1200 rodzin zidentyfikowano więcej niż 400 mutacji genu HNF1A, wśród których najczęstsze występowały w domenie odpowiedzialnej za dimeryzację i wiązanie się z DNA [12,28,35]. W dalszym ciągu w genie HNF1A identyfikowane są kolejne mutacje [27]. ...
Maturity-onset diabetes of the young (MODY) is a monogenic disorder with autosomal dominant inheritance. MODY is a rarely diagnosed form of diabetes, its incidence, depending on the population, is estimated at 1-5% of children with diabetes. MODY diabetes currently includes 14 forms of diabetes with different etiology. Each of the MODY subtypes is conditioned by a mutation in one of the 14 identified genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, APPL1. The most frequently recognized subtypes of MODY are conditioned by mutations of the HNF1A (30-65%), GCK (30-60%), HNF4A (5-10%) and HNF1B (5%) genes. MODY is characterized by the following features: 1) mild fasting hyperglycemia, 2) onset of symptoms before the age of 25, 3) lack of autoantibodies against pancreatic beta-cell antigens and features typical of type 2 diabetes (insulin resistance, obesity). Individual subtypes of MODY diabetes are characterized by a different spectrum of clinical symptoms and different age of onset. GCK gene mutations cause mild, asymptomatic fasting hyperglycemia, usually not requiring appropriate treatment. HNF1A and HNF4A gene mutations are associated with progressive pancreatic β-cell dysfunction and hyperglycemia, which may lead to microvascular complications, in the HNF1B- MODY subtype there are concomitant developmental abnormalities. In the treatment of MODY, depending on the subtype, diet, sulfonylureas or other oral hyperglycemic agents are applied and insulin therapy may be required later in life and during pregnancy. Next-generation sequencing (NGS) technique using a commercial gene panel is used in the molecular diagnosis of MODY diabetes. The knowledge of the genetic etiology of diabetes and the determination of the MODY subtype is of significant practical importance in the prognosis of the course of the disease, it allows the selection of the optimal t reatment method, it is also the basis for screening of asymptomatic family members of the patient and genetic consueling.
... These variations include missense, nonsense, frameshift, in-frame deletions/insertions/duplications, splice site, promoter region, and whole/partial gene deletions. Analyses of these variants have demonstrated that some of them render the protein unstable and poorly expressed (17,18). Some of the variants affect either the DNA binding or transactivation ability of HNF1A. ...
Background
HNF1A is an essential component of the transcription factor network that controls pancreatic β-cell differentiation, maintenance, and glucose stimulated insulin secretion (GSIS). A continuum of protein malfunction is caused by variations in the HNF1A gene, from severe loss-of-function (LOF) variants that cause the highly penetrant Maturity Onset Diabetes of the Young (MODY) to milder LOF variants that are far less penetrant but impart a population-wide risk of type 2 diabetes that is up to five times higher. Before classifying and reporting the discovered variations as relevant in clinical diagnosis, a critical review is required. Functional investigations offer substantial support for classifying a variant as pathogenic, or otherwise as advised by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) ACMG/AMP criteria for variant interpretation.
Objective
To determine the molecular basis for the variations in the HNF1A gene found in patients with monogenic diabetes in India.
Methods
We performed functional protein analyses such as transactivation, protein expression, DNA binding, nuclear localization, and glucose stimulated insulin secretion (GSIS) assay, along with structural prediction analysis for 14 HNF1A variants found in 20 patients with monogenic diabetes.
Results
Of the 14 variants, 4 (28.6%) were interpreted as pathogenic, 6 (42.8%) as likely pathogenic, 3 (21.4%) as variants of uncertain significance, and 1 (7.14%) as benign. Patients harboring the pathogenic/likely pathogenic variants were able to successfully switch from insulin to sulfonylureas (SU) making these variants clinically actionable.
Conclusion
Our findings are the first to show the need of using additive scores during molecular characterization for accurate pathogenicity evaluations of HNF1A variants in precision medicine.
... Those models showed improvement in the specificity (94% vs 91%) and sensitivity (91% vs 72%) in identifying MODY compared with the standard criteria (patient diagnosed before the age of 25 years and has an affected parent) (4). The use of Next-Generation Sequencing (NGS) methods has led to the confirmation of cases and the discovery of multiple novel MODY gene variants (5). ...
... If HbA1c is lower than 6.5%, a low carbohydrate diet may be temporarily successful. With a higher or rising HbA1c, the next useful treatment is sulfonylurea derivatives (5). Sulfonylurea derivatives increase endogenous insulin secretion, which allows the body to respond spontaneously to glycemic changes. ...
The frequent misdiagnosis of MODY (Maturity-Onset Diabetes of the Young) subtypes makes it necessary to clarify the clinical spectrum of the disease phenotypes in suspected subjects so that accurate diagnosis and management plans can be introduced as early as possible in the course of the disease. We report the case of a MODY subtype that was initially characterized as variant of uncertain significance (VUS) but was later changed to a likely pathogenic variant following our report of two cases where the full expression of the clinical phenotype was described. HNF1A-MODY (Maturity Onset Diabetes of the Young type 3) is one of the most common subtypes of MODY. Due to its variable clinical presentation, and the concerns with being misdiagnosed as either type 1 or type 2 diabetes, DNA sequencing is needed to confirm the diagnosis. This case report illustrates the clinical scenario leading to the identification of the gene variant c.416T>C(p. Leu139Pro) in the HNF1A gene, initially reported as a VUS and later upgraded to a likely pathogenic variant. Though the mutation was described in two Czech family members in 2020, the clinical course and phenotype was not characterized. Therefore, there was the need to fully describe the spectrum of the disease arising from the mutation. The case report fully describes the clinical spectrum of this mutation and provides much needed clinical management approaches to the wider scientific community.
... HNF1A-MODY Diabetes mellitus appears generally at the age of 6-25 years with modest osmotic symptoms (polyuria, polydipsia) or as asymptomatic postprandial hyperglycemia without ketosis or ketoacidosis. C-peptide readings are lower than in healthy persons, but greater than for T1D, lack of pancreatic islet antibodies (5). The HNF1A-MODY is treated differently according on the patient's age and HbA1c levels. ...
... This cross-sectional study included 20 patients diagnosed with diabetes mullites following up at Diabetes, Endocrine and Metabolism pediatric unit (DEMPU) Cairo university; Eleven females (55%) 3 of them were non-pubertal, 3 started puberty (stage 3) and 5 are pubertal, Nine males (45%) 3 of them were non-pubertal,3 started puberty (stage 4) and 3 were pubertal.. Valkovicova et al., (5) concluded that Diabetes mellitus appears generally at the age of 6-25 years with modest osmotic symptoms (polyuria, polydipsia) or as asymptomatic postprandial 0.56* -Oral hypoglycemic drugs 1 5% -Both 2 10% in 101(39%) of the patients only, came with a conclusion that GCK mutations were the most common (55.3%) followed by HNF1A (28.2%), HNF1B (9.7%), and HNF4A (6.8%). ...
Background: Maturity-onset diabetes of the young (MODY) is a group of inherited disorders of non-autoimmune diabetes mellitus which usually present in adolescence or young adulthood. Patients and Methods: This cross-sectional study included 20 patients diagnosed with diabetes mellitus following up at Diabetes, Endocrine and Metabolism pediatric unit (DEMPU) Children hospital, Cairo University. The range of patients' age was 3-18 years with mean diabetes duration of 1 year and 5 months. Genetic analysis of exon 5 of HNF1A gene was done using DNA sequencing method after a written consent was taken from the patient's guardian. Results: The mean age of patients is 12.1 years with range of 3-18 years, mean age at diagnosis 10.77 years with mean diabetes duration 1 year and 5 months and mean HBA1c is 9%. All participants have family history of diabetes in at least 3 generations most of them diagnosed before age of 35 years as well as negative auto antibody (Anti GAD and Anti islet), measurable c peptide with mean of 0.45 nmol/litre. All patients showed no mutation in Exon 5 of HNF1A. Conclusion: Clinical suspicion of MODY 3 requires studying the whole gene for 10 exons and if negative, genetic testing for GCK, HNF1B, and HNF4A is highly recommended due to similarities in phenotype.
