Monogenic diabetes is a gateway to precision medicine through molecular mechanistic insight. Hepatocyte nuclear factor 1A (HNF-1A) and HNF-4A are transcription factors that engage in crossregulatory gene transcription networks to maintain glucose-stimulated insulin secretion in pancreatic β cells. Variants in the HNF1A and HNF4A genes are associated with maturity-onset diabetes of the young (MODY). Here, we explored 4 variants in the P2-HNF4A promoter region: 3 in the HNF-1A binding site and 1 close to the site, which were identified in 63 individuals from 21 families of different MODY disease registries across Europe. Our goal was to study the disease causality for these variants and to investigate diabetes mechanisms on the molecular level. We solved a crystal structure of HNF-1A bound to the P2-HNF4A promoter and established a set of techniques to probe HNF-1A binding and transcriptional activity toward different promoter variants. We used isothermal titration calorimetry, biolayer interferometry, x-ray crystallography, and transactivation assays, which revealed changes in HNF-1A binding or transcriptional activities for all 4 P2-HNF4A variants. Our results suggest distinct disease mechanisms of the promoter variants, which can be correlated with clinical phenotype, such as age of diagnosis of diabetes, and be important tools for clinical utility in precision medicine.

• MeSH
• diabetes mellitus 2. typu * genetika   metabolismus   MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   metabolismus   MeSH
• hepatocytární jaderný faktor 4 * genetika   metabolismus   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• promotorové oblasti (genetika) * genetika   MeSH
• regulace genové exprese MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• diabetes mellitus 2. typu * genetika   MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• mutace MeSH
• penetrance MeSH
• porodní hmotnost genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

BACKGROUND: HNF1A-MODY is a monogenic form of diabetes caused by variants in the HNF1A gene. Different HNF1A variants are associated with differences in age of disease onset, but other factors are postulated to influence this trait. Here, we searched for genetic variants influencing age of HNF1A-MODY onset. METHODS: Blood samples from 843 HNF1A-MODY patients from Czech Republic, France, Poland, Slovakia, the UK and the US were collected. A validation set consisted of 121 patients from the US. We conducted a genome-wide association study in 843 HNF1A-MODY patients. Samples were genotyped using Illumina Human Core arrays. The core analysis was performed using the GENESIS package in R statistical software. Kinship coefficients were estimated with the KING and PC-Relate algorithms. In the linear mixed model, we accounted for year of birth, sex, and location of the HNF1A causative variant. RESULTS: A suggestive association with age of disease onset was observed for rs2305198 (p = 2.09E-07) and rs7079157 (p = 3.96E-06) in the HK1 gene, rs2637248 in the LRMDA gene (p = 2.44E-05), and intergenic variant rs2825115 (p = 2.04E-05). Variant rs2637248 reached nominal significance (p = 0.019), while rs7079157 (p = 0.058) and rs2825115 (p = 0.068) showed suggestive association with age at diabetes onset in the validation set. CONCLUSIONS: rs2637248 in the LRMDA gene is associated with age at diabetes onset in HNF1A-MODY patients.

• MeSH
• celogenomová asociační studie * MeSH
• diabetes mellitus 2. typu * diagnóza   genetika   MeSH
• fenotyp MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Maturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. CASE REPORT: A female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. CONCLUSION: Digenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.

• MeSH
• cystická onemocnění ledvin genetika   patologie   MeSH
• diabetes mellitus 2. typu genetika   patologie   MeSH
• dítě MeSH
• fenotyp MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• heterozygot MeSH
• lidé MeSH
• mutace MeSH
• nemoci ledvin genetika   patologie   MeSH
• uterus abnormality   MeSH
• vrozené poruchy tubulárního transportu genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• Klíčová slova
• MODY,
• MeSH
• biologické markery * analýza   MeSH
• diabetes mellitus genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   MeSH
• lidé MeSH
• následné studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH

CONTEXT: While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. OBJECTIVE: We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. DESIGN, SETTINGS, AND PARTICIPANTS: We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). RESULTS: Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants. CONCLUSION: Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes.

• MeSH
• biologické markery analýza   MeSH
• diabetes mellitus 1. typu genetika   metabolismus   patologie   MeSH
• diabetes mellitus 2. typu genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• fenotyp MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• lidé MeSH
• mutace * MeSH
• následné studie MeSH
• prognóza MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• celogenomová asociační studie MeSH
• dna (nemoc) krev   epidemiologie   genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické lokusy MeSH
• genetické markery * MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• játra metabolismus   patologie   MeSH
• jednonukleotidový polymorfismus * MeSH
• kardiovaskulární nemoci krev   epidemiologie   genetika   MeSH
• kohortové studie MeSH
• kyselina močová krev   MeSH
• ledviny metabolismus   patologie   MeSH
• lidé MeSH
• metabolické nemoci krev   epidemiologie   genetika   MeSH
• nádorové proteiny genetika   MeSH
• orgánová specificita MeSH
• signální transdukce * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Hepatocellular adenoma (HA) is a benign neoplasm of the liver, whose aetiopathogenesis is little known. Newest research allowed dividing all cases into three types based on molecular characteristics: inflammatory HA, HA with HNF1A mutation, β-catenin-mutated HA. The clinical significance of HA is chiefly due to the possibility of malignant transformation into hepatocellular carcinoma (HCC). The aim of the present study was to immunohistochemically assess the expression pattern and level of c-MET protein in hepatocellular adenoma (taking into account its status of Wnt/β-catenin pathway functioning) and intertwining the results into a wider pattern of expression in non-neoplastic liver and hepatocellular carcinoma of various histological grades. It was found that expression of c-MET in poorly-differentiated HCC was significantly higher than in non-neoplastic liver and well- to moderately-differentiated HCC. The expression in HA was variable and differed between molecular subtypes of this neoplasm: inflammatory and HNF1A mutation-associated type are characterized by overexpression of c-MET to an extent comparable with poorly-differentiated HCC, whereas Wnt/β-catenin dysfunction-associated type lacks overexpression, and the amount of c-MET protein accumulated in its cells is similar to the levels in non-neoplastic tissue and well- to moderately-differentiated HCC. These findings suggest that c-MET overexpression in HA is not an early event in hepatocarcinogenesis, but constitutes a divergent molecular pathway leading to neoplastic change compared to overexpression observed in the late stages of tumour progression.

• MeSH
• dospělí MeSH
• hepatocelulární karcinom metabolismus   MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• imunohistochemie MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• mutace MeSH
• nádory jater metabolismus   MeSH
• protoonkogenní proteiny c-met metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

LADA a MODY jsou často se vyskytující formy diabetu, které se liší svou etiologií, terapií i prognózou. V určitých fázích svého vývoje však sdílejí některé charakteristiky. Stanovení správné etiologické diagnózy je naprosto zásadní pro výběr adekvátní terapie, dosažení uspokojivé kompenzace a prevenci pozdních komplikací diabetu.

LADA and MODY are frequently occurring forms of diabetes of different etiology, treatment and prognosis, that may share some common clinical characteristics. This article highlights the importance of correct etiological diagnostic as a key prerequisite for a disease-tailored treatment and improvement of diabetes control.

• Klíčová slova
• HNF-diabetes, autoimunitní diabetes, glukokinázový diabetes (GCK-MODY), Latent Autoimmune Diabetes in Adults, Maturity Onset Diabetes of the Young,
• MeSH
• autoprotilátky MeSH
• diabetes mellitus 1. typu * diagnóza   etiologie   farmakoterapie   genetika   MeSH
• diabetes mellitus 2. typu * diagnóza   etiologie   farmakoterapie   genetika   MeSH
• diabetická ketoacidóza diagnóza   MeSH
• diferenciální diagnóza MeSH
• glukokinasa * genetika   MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• hyperglykemie diagnóza   etiologie   MeSH
• hypoglykemika terapeutické užití   MeSH
• inzulin terapeutické užití   MeSH
• lidé MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

OBJECTIVES: Sulfonylurea derivatives are widely used for clinical treatment of human subjects with Maturity Onset Diabetes of the Young (MODY) caused by mutations in HNF-1α or HNF-4α despite the mechanism leading to their hypersensitivity is incompletely understood. In Hnf1a(-/-) mice, serum concentrations and half-life of sulfonylurea derivatives are strongly increased. We thus hypothesized that reduced sulfonylurea derivatives clearance stands behind their therapeutic potential in human HNF1A/HNF4A MODY subjects. DESIGN AND METHODS: Single doses of 3 mg glipizide and 5 mg glibenclamide/glyburide were administered sequentially to seven HNF1A/HNF4A MODY subjects and six control individuals matched for their age, BMI and CYP2C9 genotype. Pharmacokinetic (plasma concentration levels, Cmax, tmax, t1/2, AUC) and pharmacodynamic parameters (glycemia, C-peptide and insulin plasma levels) were followed for 24 hours after drug administration. RESULTS: We provide the first evidence on the pharmacokinetics and pharmacodynamics of sulfonylurea derivatives in human MODY subjects. The half-life of glipizide did not change, and reached 3.8±0.7 and 3.7±1.8 h in the MODY and control subjects, respectively. The half-life of glibenclamide was increased only in some MODY subjects (t1/2 9.5±6.7 and 5.0±1.4 h, respectively). Importantly, the intra- individual responses of MODY (but control) subjects to glipizide and glibenclamide treatment were highly correlated. With regards to pharmacodynamics, we observed a differential response of control but not MODY subjects to the doses of glipizide and glibenclamide applied. CONCLUSIONS: We rejected the hypothesis that all human MODY-associated mutations in HNF1A / HNF4A induce changes in the pharmacokinetics of sulfonylureas in humans analogically to the Hnf1a(-/-) mouse model.

• MeSH
• diabetes mellitus 2. typu farmakoterapie   genetika   metabolismus   MeSH
• dospělí MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• modely nemocí na zvířatech * MeSH
• myši knockoutované MeSH
• myši MeSH
• poločas MeSH
• studie případů a kontrol MeSH
• sulfonylmočovinové sloučeniny škodlivé účinky   farmakokinetika   MeSH
• zárodečné mutace MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH