INTRODUCTION: Neonatal hypoglycaemia is the most common metabolic disorder of various causes, relatively rare being MODY (Maturity Onset Diabetes of the Young). CONTENT: Data search of relevant articles focused on hypoglycaemia in carriers of selected MODY gene mutations published from 2007 to 2022 was performed in databases Medline, PubMed, Cochrane and UptoDate based on key words: 'hyperinsulinemic hypoglycaemia', 'congenital hyperinsulinism', 'MODY', 'HNF4A mutation', 'HNF1A mutation'. SUMMARY: Loss of function of HNF4A and HNF1A genes comprises approximately to 5.9 % of diazoxide responsive hyperinsulinemic hypoglycaemia, which may appear in 15 % HNF4A mutation carriers. A typical finding of HNF4A mutation carriers with neonatal hypoglycaemia was a birth weight above 4000 g or above 97th percentile. OUTLOOK: Although mutations in MODY genes represent a rare cause of neonatal hypoglycaemia, they should be considered in the differential diagnosis, particularly in cases of persistent hypoglycaemia requiring intensive care.

• Klíčová slova
• HNF1A, HNF4A, MODY, congenital hyperinsulinism, hyperinsulinemic hypoglycemia,
• MeSH
• diabetes mellitus 2. typu * genetika   komplikace   MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 * genetika   MeSH
• hypoglykemie * genetika   etiologie   patologie   MeSH
• lidé MeSH
• mutace * MeSH
• nemoci novorozenců * genetika   MeSH
• novorozenec MeSH
• rodiče MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 * MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč

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.

• Klíčová slova
• Diabetes, Metabolism, Structural biology, Transcription,
• 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
• Názvy látek
• hepatocytární jaderný faktor 1-alfa * MeSH
• hepatocytární jaderný faktor 4 * MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč

• Klíčová slova
• Birthweight, Hepatocyte nuclear factor-4 alpha (HNF4A), Maturity-onset diabetes of the young (MODY), Penetrance,
• 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
• Názvy látek
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF4A protein, human MeSH Prohlížeč

Prediction methods have become an integral part of biomedical and biotechnological research. However, their clinical interpretations are largely based on biochemical or molecular data, but not clinical data. Here, we focus on improving the reliability and clinical applicability of prediction algorithms. We assembled and curated two large non-overlapping large databases of clinical phenotypes. These phenotypes were caused by missense variations in 44 and 63 genes associated with Mendelian diseases. We used these databases to establish and validate the model, allowing us to improve the predictions obtained from EVmutation, SNAP2 and PoPMuSiC 2.1. The predictions of clinical effects suffered from a lack of specificity, which appears to be the common constraint of all recently used prediction methods, although predictions mediated by these methods are associated with nearly absolute sensitivity. We introduced evidence-based tailoring of the default settings of the prediction methods; this tailoring substantially improved the prediction outcomes. Additionally, the comparisons of the clinically observed and theoretical variations led to the identification of large previously unreported pools of variations that were under negative selection during molecular evolution. The evolutionary variation analysis approach described here is the first to enable the highly specific identification of likely disease-causing missense variations that have not yet been associated with any clinical phenotype.

• MeSH
• algoritmy MeSH
• ektodysplasiny genetika   MeSH
• fenotyp MeSH
• genetická variace MeSH
• genetické nemoci vrozené genetika   MeSH
• genomika MeSH
• glukosa-6-fosfátdehydrogenasa genetika   MeSH
• hemoglobiny genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• lidé MeSH
• missense mutace MeSH
• modely genetické * MeSH
• molekulární evoluce MeSH
• mutace * MeSH
• pravděpodobnostní funkce MeSH
• proteomika MeSH
• tyrosinfosfatasa nereceptorového typu 11 genetika   MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• EDA protein, human MeSH Prohlížeč
• ektodysplasiny MeSH
• G6PD protein, human MeSH Prohlížeč
• glukosa-6-fosfátdehydrogenasa MeSH
• hemoglobin B MeSH Prohlížeč
• hemoglobiny MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF4A protein, human MeSH Prohlížeč
• PTPN11 protein, human MeSH Prohlížeč
• tyrosinfosfatasa nereceptorového typu 11 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
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• genetické markery * MeSH
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč
• kyselina močová MeSH
• nádorové proteiny MeSH

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

• MeSH
• celogenomová asociační studie MeSH
• databáze genetické MeSH
• duktální karcinom slinivky břišní genetika   MeSH
• genetická predispozice k nemoci MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• intracelulární signální peptidy a proteiny MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• nádory slinivky břišní genetika   MeSH
• proteiny genetika   MeSH
• represorové proteiny genetika   MeSH
• tensiny genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-beta MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF1B protein, human MeSH Prohlížeč
• HNF4G protein, human MeSH Prohlížeč
• intracelulární signální peptidy a proteiny MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• NOC2L protein, human MeSH Prohlížeč
• proteiny MeSH
• represorové proteiny MeSH
• tensiny MeSH
• TNS3 protein, human MeSH Prohlížeč
• Ucma protein, human MeSH Prohlížeč

HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations.

• MeSH
• diabetes mellitus 2. typu farmakoterapie   genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci genetika   MeSH
• haplotypy genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• hypoglykemika terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace genetika   MeSH
• odds ratio MeSH
• porodní hmotnost genetika   fyziologie   MeSH
• senioři MeSH
• sulfonylmočovinové sloučeniny terapeutické užití   MeSH
• výpočetní biologie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hepatocytární jaderný faktor 4 MeSH
• hypoglykemika MeSH
• sulfonylmočovinové sloučeniny MeSH

CONTEXT: Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic β-cells causing severe hypoglycemia. OBJECTIVE: We studied the distribution of genetic causes of CHI in a Czech population. METHODS: Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. RESULTS: We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41-91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. CONCLUSION: We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations.

• MeSH
• aktivace transkripce MeSH
• DNA genetika   MeSH
• dospělí MeSH
• draslíkové kanály dovnitř usměrňující genetika   MeSH
• genetická variace MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• kinázy zárodečného centra MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mutace genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protein-serin-threoninkinasy genetika   MeSH
• radioizotopy rubidia MeSH
• receptory sulfonylurey genetika   MeSH
• rodokmen MeSH
• těhotenství MeSH
• vrozený hyperinzulinismus epidemiologie   genetika   MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• ABCC8 protein, human MeSH Prohlížeč
• DNA MeSH
• draslíkové kanály dovnitř usměrňující MeSH
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč
• kinázy zárodečného centra MeSH
• Kir6.2 channel MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• radioizotopy rubidia MeSH
• receptory sulfonylurey 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
• Názvy látek
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč
• sulfonylmočovinové sloučeniny MeSH

AIMS: Islet cell autoantibodies are associated with autoimmune insulitis and belong to the diagnostic criteria of type 1 diabetes mellitus. However, growing evidence suggests that autoantibodies are present in other types of diabetes. Here, we focus on the autoantibody incidence in Czech patients with maturity-onset diabetes of the young and analyse their functional relevance in terms of diabetes onset and control. METHODS: Autoantibodies against glutamic acid decarboxylase (GAD) 65 and protein tyrosine phosphatase islet antigen 2 (IA-2) were measured in a cohort of 28 Czech patients with maturity-onset diabetes of the young, all confirmed by genetic testing. Selected clinical data were correlated to the status and kinetics of autoantibodies. RESULTS: One quarter of patients with maturity-onset diabetes of the young examined (7/28; 25%) was positive for GAD or IA-2 autoantibodies. GAD autoantibodies were more prevalent (7/7) than IA-2 autoantibodies (1/7). The incidence of autoantibodies did not correlate with human leukocyte antigen status. The patients who were positive for the autoantibodies developed diabetes later than those who were autoantibody-negative, but had worse glycaemic control (increased HbA1c ). Expression of autoantibodies decreased with any improvement of diabetes compensation. Only one patient did not correspond to the above and displayed signs of combined signs of maturity-onset diabetes of the young and Type 1 diabetes. CONCLUSIONS: The data suggest transient but highly prevalent islet cell autoantibody expression in Czech patients with maturity-onset diabetes of the young. The autoantibodies were found in patients with delayed diabetes onset, and in times of insufficient diabetes control. As improvement of glycaemic control was associated with a decrease in levels of autoantibodies, their presence may reflect the kinetics of β-cell destruction induced by causes other than autoimmune ones.

• MeSH
• autoprotilátky imunologie   MeSH
• diabetes mellitus 2. typu epidemiologie   imunologie   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• glukokinasa genetika   MeSH
• glutamát dekarboxyláza imunologie   MeSH
• glykovaný hemoglobin metabolismus   MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• kohortové studie MeSH
• Langerhansovy ostrůvky imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• tyrosinfosfatasy receptorového typu, třída 8 imunologie   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoprotilátky MeSH
• glukokinasa MeSH
• glutamát dekarboxyláza MeSH
• glykovaný hemoglobin MeSH
• hemoglobin A1c protein, human MeSH Prohlížeč
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč
• tyrosinfosfatasy receptorového typu, třída 8 MeSH