RACD – syndrom renálních cyst a diabetu (MODY 5) je vzácným projevem tzv. monogenního diabetu. Je spojen s transkripčním faktorem HNF-1b a souvisí s bodovými mutacemi a popřípadě s delecemi genu HNF-1b. V naší kazuistice prezentujeme diagnostický a terapeutický proces u předčasně narozeného chlapečka, jehož příběh začíná u jeho maminky. Pacientka byla od 18 let léčena inzulínem pro diabetes mellitus 1. typu. V době těhotenství ji byla diagnóza na základě genetického vyšetření korigována na MODY 5. Toto bylo indikováno pro přítomnost renálních cyst plodu viditelných na ultrasonografickém a následném MR vyšetření. Stejné onemocnění bylo prokázáno i u jejího dítěte, které již od narození bylo léčena inzulínem a monitorováno pomocí CGM systému. Inzulín byl aplikován v ředěné formě a podáván inzulínovou pumpou. Jeho potřeba postupně klesala koncem 1. roku věku a mohl být na přechodnou dobu vysazen.

RACD – renal cysts and diabetes syndrome (MODY 5) is a rare manifestation of so-called monogenic diabetes. It is associated with the transcription factor HNF-1b and is associated with point mutations and, optionally, deletions in the HNF-1b gene. In our case report, we present a diagnostic and therapeutic process in a premature baby boy, whose story begins with his mother. The patient was treated with insulin for type 1 diabetes mellitus from the age of 18. At the time of pregnancy, her diagnosis was corrected to MODY 5 on the basis of genetic examination. This was indicated for the presence of foetal renal cysts visible on ultrasonographic and subsequent MR examination. The same disease was demonstrated in her child, who was treated with insulin from birth and monitored using the CGM system. Insulin was administered in diluted form and administered by insulin pump. His need gradually decreased at the end of the first year of age and the treatment could be suspended for a temporary period.

• Klíčová slova
• MODY,
• MeSH
• cystická onemocnění ledvin etiologie   MeSH
• delece genu MeSH
• diabetes mellitus * etiologie   terapie   MeSH
• diagnostické zobrazování MeSH
• dospělí MeSH
• hepatocytární jaderný faktor 1-beta genetika   nedostatek   MeSH
• inzulinové infuzní systémy MeSH
• lidé MeSH
• novorozenec * MeSH
• předčasný porod MeSH
• renální hypertenze MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec * MeSH
• ženské pohlaví MeSH

Hepatocyte nuclear factor-1-beta (HNF1B) is a transcription factor and putative biomarker of solid tumours. Recently, we have revealed a variety of HNF1B mRNA alternative splicing variants (ASVs) with unknown, but potentially regulatory, functions. The aim of our work was to quantify the most common variants and compare their expression in tumour and non-tumour tissues of the large intestine, prostate, and kidney. The HNF1B mRNA variants 3p, Δ7, Δ7-8, and Δ8 were expressed across all the analysed tissues in 28.2-33.5%, 1.5-2%, 0.8-1.7%, and 2.3-6.9% of overall HNF1B mRNA expression, respectively, and occurred individually or in combination. The quantitative changes of ASVs between tumour and non-tumour tissue were observed for the large intestine (3p, Δ7-8), prostate (3p), and kidney samples (Δ7). Decreased expression of the overall HNF1B mRNA in the large intestine and prostate cancer samples compared with the corresponding non-tumour samples was observed (p = 0.019 and p = 0.047, respectively). The decreased mRNA expression correlated with decreased protein expression in large intestine carcinomas (p < 0.001). The qualitative and quantitative pattern of the ASVs studied by droplet digital PCR was confirmed by next-generation sequencing, which suggests the significance of the NGS approach for further massive evaluation of the splicing patterns in a variety of genes.

• MeSH
• alternativní sestřih * MeSH
• hepatocytární jaderný faktor 1-beta genetika   metabolismus   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory genetika   metabolismus   MeSH
• polymerázová řetězová reakce MeSH
• protein - isoformy MeSH
• regulace genové exprese u nádorů MeSH
• retrospektivní studie MeSH
• RNA nádorová genetika   metabolismus   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie 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

Hepatocyte nuclear factor 1 beta (HNF1B) is a transcription factor which plays a crucial role in nephronogenesis, and its germline mutations have been associated with kidney developmental disorders. However, the effects of HNF1B somatic exonic mutations and its role in the pathogenesis of kidney tumours has not yet been elucidated. Depending on the type of the tumour HNF1B may act as a tumour suppressor or oncogene, although the exact mechanism by which HNF1B participates in the process of cancerogenesis is unknown. Using an immunohistochemical approach, and methylation and mutation analysis, we have investigated the expression, epigenetic, and genetic changes of HNF1B in 130 cases of renal tumours (121 renal cell carcinomas, 9 oncocytomas). In the subset of clear cell renal cell carcinoma (ccRCC), decreased HNF1B expression was associated with a higher tumour grade and higher T stage. The mutation analysis revealed no mutations in the analysed samples. Promoter methylation was detected in two ccRCCs and one oncocytoma. The results of our work on a limited sample set suggest that while in papillary renal cell carcinoma HNF1B functions as an oncogene, in ccRCC and chRCC it may act in a tumour suppressive fashion.

• MeSH
• epigeneze genetická genetika   MeSH
• epigenomika metody   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• karcinom z renálních buněk genetika   patologie   MeSH
• ledviny patologie   MeSH
• lidé MeSH
• mutační analýza DNA metody   MeSH
• nádory ledvin genetika   patologie   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors. In our study we focused on analyzing HNF1B in prostate carcinoma (PC) and adenomyomatous hyperplasia (AH), as well as its possible relation to the upstream gene EZH2 and downstream gene ECI2. The results of our study showed that on an immunohistochemical level, the expression of HNF1B was low in PC, did not differ between PC and AH, and did not correlate with any clinical outcomes. In PC, mutations of HNF1B gene were rare, but the methylation of its promotor was a common finding and was positively correlated with Gleason score and stage. The relationship between HNF1B and EZH2/ECI2 was equivocal, but EZH2 and ECI2 were positively correlated on both mRNA and protein level. The expression of EZH2 was associated with poor prognosis. ECI2 did not correlate with any clinical outcomes. Our results support the oncosuppressive role of HNF1B in PC, which may be silenced by promotor methylation and other mechanisms, but not by gene mutation. The high expression of EZH2 (especially) and ECI2 in PC seems to be a potential therapeutic target.

• MeSH
• enoyl-CoA-izomeráza genetika   metabolismus   MeSH
• EZH2 protein genetika   metabolismus   MeSH
• hepatocytární jaderný faktor 1-beta genetika   metabolismus   MeSH
• hyperplazie prostaty genetika   metabolismus   patologie   MeSH
• imunohistochemie metody   MeSH
• kohortové studie MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• metylace DNA MeSH
• mutace MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• prognóza MeSH
• promotorové oblasti (genetika) MeSH
• prostata patologie   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• stupeň nádoru MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cystic kidney diseases are a very heterogeneous group of chronic kidney diseases. The diagnosis is usually based on clinical and ultrasound characteristics and the final diagnosis is often difficult to be made. Next-generation sequencing (NGS) may help the clinicians to find the correct final diagnosis. The aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with cystic kidney diseases. Next-generation sequencing of genes responsible for the formation of cystic kidneys was performed in 31 unrelated patients with various clinically diagnosed cystic kidney diseases gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one (in case of autosomal recessive inheritance) pathogenic variant was found in 29% of patients (n = 9). The result of NGS correlated with the clinical diagnosis made before the NGS in 55% of patients (n = 17), in the remaining 14 children (45%) the result of NGS revealed another type of cystic kidney disease that was suspected clinically before or did not find causal mutation in suspected genes. The most common unexpected findings were variants in nephronophthisis (NPHP) genes in children with clinically suspected autosomal recessive polycystic kidney disease (ARPKD, n = 4). Overall, 24 pathogenic or probably pathogenic variants were detected in the PKHD1 gene, 8 variants in the TMEM67 gene, 4 variants in the PKD1 gene, 2 variants in the HNF1B gene and 2 variants in BBS1 and NPHP1 genes, respectively. NGS is a valuable tool in the diagnostics of various forms of cystic kidney diseases. Its results changed the clinically based diagnoses in 16% (n = 5) of the children.

• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• cystická onemocnění ledvin diagnóza   genetika   MeSH
• cytoskeletální proteiny genetika   MeSH
• dítě MeSH
• genetická predispozice k nemoci genetika   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• kationtové kanály TRPP genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mutace * MeSH
• novorozenec MeSH
• polycystické ledviny autozomálně recesivní diagnóza   genetika   MeSH
• předškolní dítě MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• receptory buněčného povrchu genetika   MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Hepatocyte nuclear factor 1 beta (HNF1B) is transcription factor which plays a crucial role in the regulation of the development of several organs, but also seems to be implicated in the development of certain tumours, especially the subset of clear cell carcinomas of the ovary and kidney. Depending on the type of the tumour, HNF1B may act as either a tumour suppressor or an oncogene, although the exact mechanism by which HNF1B participates in the process of cancerogenesis is unknown. Using immunohistochemical approach and methylation and mutation analysis, we have investigated the expression, epigenetic, and genetic changes of HNF1B on 40 cases of colorectal adenomas and 105 cases of colorectal carcinomas. The expression of HNF1B was correlated with the benign or malignant behaviour of the lesion, given that carcinomas showed significantly lower levels of expression compared to adenomas. In carcinomas, lower levels of HNF1B expression were associated with recurrence and shortened disease-free survival. The mutation analysis revealed three somatic mutations (two frameshift and one nonsense) in the carcinoma sample set. Promoter methylation was detected in three carcinomas. These results suggest that in colorectal cancer, HNF1B may play a part in the pathogenesis and act in a tumour suppressive fashion.

• MeSH
• epigeneze genetická * MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• kolorektální nádory genetika   metabolismus   patologie   MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   metabolismus   patologie   MeSH
• metylace DNA * MeSH
• míra přežití MeSH
• nádorové biomarkery genetika   MeSH
• následné studie MeSH
• prognóza MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u nádorů * MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Hepatocyte nuclear factor-1-beta (HNF1B) is a transcription factor crucial for the development of several tissues, and a promising biomarker of certain solid tumours. Thus far, two HNF1B alternative splicing variants (ASVs) have been described, however, the complete spectrum, prevalence and role of HNF1B ASVs in tumorigenesis are unclear. Considering the equivocal data about HNF1B ASVs and expression presented in literature, our aim was to characterize the spectrum of HNF1B mRNA splicing variants across different tissues. Here, we characterize HNF1B ASVs with high sensitivity in carcinomas of the uterine corpus, large intestine, kidney, pancreas, and prostate, with selected paired healthy tissues, using the previously described multiplex PCR and NGS approach. We identified 45 ASVs, of which 43 were novel. The spectrum and relative quantity of expressed ASVs mRNA differed among the analysed tissue types. Two known (3p, Δ7_8) and two novel (Δ7, Δ8) ASVs with unknown biological functions were detected in all the analysed tissues in a higher proportion. Our study reveals the wide spectrum of HNF1B ASVs in selected tissues. Characterization of the HNF1B ASVs is an important prerequisite for further expression studies to delineate the HNF1B splicing pattern, potential ASVs functional impact, and eventual refinement of HNF1B's biomarker role.

• MeSH
• alternativní sestřih genetika   MeSH
• biologické markery metabolismus   MeSH
• hepatocytární jaderný faktor 1-beta genetika   metabolismus   MeSH
• ledviny metabolismus   patologie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• multiplexová polymerázová řetězová reakce MeSH
• pankreas metabolismus   patologie   MeSH
• sestřih RNA genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

• MeSH
• chronické selhání ledvin epidemiologie   genetika   patologie   MeSH
• dominantní geny * MeSH
• dospělí MeSH
• genetické testování statistika a číselné údaje   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• ledvinové kanálky patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mucin 1 genetika   MeSH
• mutace MeSH
• prevalence MeSH
• průřezové studie MeSH
• senioři MeSH
• uromodulin genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Irsko MeSH

BACKGROUND: HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult. METHODS: Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases. RESULTS: Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of - 0.33 ml/min/1.73m2 per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was - 2.8 ml/min/1.73m2 (± 13.2), in the total cohort - 1.0 ml/min/1.73m2 (±10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases. CONCLUSIONS: In most children, HNF1B nephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease.

• MeSH
• chronické selhání ledvin genetika   MeSH
• dítě MeSH
• fenotyp MeSH
• genetické asociační studie MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• novorozenec MeSH
• polycystická choroba ledvin genetika   patologie   patofyziologie   MeSH
• předškolní dítě MeSH
• progrese nemoci MeSH
• registrace MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Německo MeSH