Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 354
Filtrar
1.
Medicine (Baltimore) ; 99(31): e21438, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756155

RESUMO

RATIONALE: Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene result in a very variable presentation, including maturity onset diabetes of the young (MODY), renal cysts, renal dysplasia, and autosomal dominant tubulointerstitial kidney disease (ADTKD), which is characterized by tubular damage, renal fibrosis, and progressive renal dysfunction. PATIENT CONCERNS: A 22-year-old man came to the hospital presenting with hyperglycemia, hyperuricemia and elevated serum creatinine. His urine protein was within the normal range. The ultrasound examination revealed shrunken kidneys with renal cysts. The patient's mother was diagnosed with diabetes mellitus when she was 25 years old. Her laboratory results showed elevated serum creatinine. Her ultrasonography revealed shrunken kidneys with renal cysts and hydronephrosis without kidney stones. The next-generation sequencing revealed that the proband and his mother held the same heterozygous missense mutation (c.530G>A, NM_000458, p.R177Q) in the HNF1B gene. Bioinformatic analyses predicted that the mutation was likely pathogenic. DIAGNOSIS: The patient and his mother were diagnosed as ADTKD and MODY5 due to HNF1B mutation. INTERVENTION: The proband was administered metformin at a dose of 500 mg/day. OUTCOMES: The patient had well-controlled blood glucose levels and a stable renal function at his 12-month follow-up. LESSONS: We should take into account the diagnoses of ADTKD and MODY5 if patients present with early onset diabetes and multiple renal cysts or evidence of renal tubulointerstitial dysplasia, especially those with negative proteinuria results. Genetic testing helps detect the HNF1B gene mutations.


Assuntos
Doenças do Sistema Nervoso Central/genética , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Nefrite Intersticial/genética , Assistência ao Convalescente , Doenças do Sistema Nervoso Central/complicações , Doenças do Sistema Nervoso Central/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Hiperglicemia/etiologia , Hiperuricemia/etiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Rim/diagnóstico por imagem , Rim/patologia , Rim/fisiopatologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/tratamento farmacológico , Doenças Renais Císticas/patologia , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Mutação de Sentido Incorreto , Nefrite Intersticial/complicações , Nefrite Intersticial/patologia , Linhagem , Ultrassonografia/métodos , Adulto Jovem
2.
Mol Carcinog ; 59(8): 989-999, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32495507

RESUMO

The effects of hepatocyte nuclear factors (HNFs) have been established in various tumors; however, the roles of HNF-1ß in colorectal cancer progression are never been found. In the present study, HNF-1ß expression was initially detected in clinical tissue samples and online datasets and HNF-1ß was found to be highly expressed in colorectal cancer tissues. In addition, a positive correlation existed between HNF-1ß expression and the overall survival of patients with colorectal cancer. In vitro and in vivo experiments revealed that HNF-1ß suppressed the stemness and migration of colorectal cancer cells. Combined with microRNAs (miRNAs) based on transcriptome-sequencing analysis, mechanistic studies showed that HNF-1ß directly bound to miR-200b promoter and thus promoted miR-200b expression, this HNF-1ß/miR-200b resulted in the downregulation of the expression of miR-200b downstream effectors. Furthermore, HNF-1ß inhibits the stemness and migration of colorectal cancer cells through miR-200b. This study reveals a novel HNF-1ß/miR-200b axis responsible for the stemness of colorectal cancer cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/metabolismo , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Transcriptoma , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
PLoS One ; 15(6): e0235071, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574212

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Renais Císticas/genética , Mutação , Rim Policístico Autossômico Recessivo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Criança , Pré-Escolar , Proteínas do Citoesqueleto/genética , República Tcheca , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/diagnóstico , Masculino , Proteínas Associadas aos Microtúbulos/genética , Rim Policístico Autossômico Recessivo/diagnóstico , Receptores de Superfície Celular/genética , Canais de Cátion TRPP/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 397-400, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219821

RESUMO

OBJECTIVE: To explore the genetic etiology of three pedigrees with a gestational history of fetal renal anomalies. METHODS: Peripheral venous blood or skin samples were derived from the probands of the three pedigrees. Copy number variation sequencing (CNV-seq) was applied to detect alterations of genome CNVs. RESULTS: The patient from pedigree 1 and the fetuses from pedigrees 2 and 3 all carried a heterozygous 17q12 deletion, with the size ranging from 1.4 Mb to 1.48 Mb encompassing the HNF1B gene. CONCLUSION: The diagnosis of 17q12 microdeletion may be difficult during fetal period for its variable phenotypes. Alterations of chromosomal copy numbers need to be excluded in such patients.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Variações do Número de Cópias de DNA , Testes Genéticos , Linhagem , Feto , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Fenótipo
5.
BMC Med Genet ; 21(1): 24, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028929

RESUMO

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of hereditary diabetes, generally caused by one abnormal gene. MODY5 is caused by mutations of the hepatocyte nuclear factor 1 homeobox ß gene (HNF1ß), always as a part of Chr17q12 deletion, whereas heterozygous mutation in B lymphocyte kinase (BLK) gene is responsible for MODY11. CASE PRESENTATION: We report a patient who developed diabetes with a 1.58-Mb Chr17q12 microdeletion and BLK gene c.211G > A mutation using the cytoscan high-density array and whole-exome sequencing analysis. The patient received the surgery at five days after birth for the duodenal atresia and had normal growth postoperatively. Mild elevated liver enzymes were found along with the normal renal function. Quantitative analysis of ß-cell function markers, including fasting insulin (< 0.2 mIU/L), fasting C-peptide (0.02 µg/L), postprandial-2 h insulin (< 0.2 mIU/L), and postprandial-2 h C-peptide (0.03 µg/L) suggested a severe loss of insulin secreting capacity. Meanwhile, islet autoantibodies (GADA, IA-2, ICA, and IAA) in the patient's blood appeared negative. Neither dysplasia in other tissues nor abnormality in development and behavior was found. CONCLUSION: To date, gastrointestinal malformations were extremely rarely reported in patients with MODY. Our clinical report further expands the clinical presentation and variability of MODY5.


Assuntos
Diabetes Mellitus Tipo 2/genética , Obstrução Duodenal/genética , Fator 1-beta Nuclear de Hepatócito/genética , Atresia Intestinal/genética , Quinases da Família src/genética , Diabetes Mellitus Tipo 2/patologia , Obstrução Duodenal/patologia , Feminino , Humanos , Recém-Nascido , Insulina/genética , Atresia Intestinal/patologia , Masculino , Mutação/genética , Fenótipo
6.
Indian J Pathol Microbiol ; 63(1): 49-52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031122

RESUMO

Background: Alpha-methylacyl-coenzyme A racemase (AMACR, P504S) is a commonly used marker in immunohistochemical diagnosis of prostate cancer. Recent studies identified P504S markers of the clear cell histotype in the ovary and/or endometrium. Gastric-type adenocarcinoma (GAS) is difficult to diagnose histologically, particularly when there is crossover with clear cell carcinoma (CCC). However, the significance of P504S for differentially diagnosing GAS and CCC is unclear. Aim: To evaluate P504S as a potential diagnostic marker of GAS and CCC. Settings and Design: We analyzed P504S expression in 48 cervical carcinomas (32 GAS and 16 CCC), as well as the expression of other markers including hepatocyte nuclear factor-1 beta (HNF-1ß) and NapsinA. Material and Methods: The expression differences of HNF-1ß, NapsinA, and P504S in GAS and CCC were detected by immunohistochemistry. Immunohistochemical histoscores based on the intensity and extent of staining were calculated. Results: The positive rates of HNF-1ß in GAS and CCC were 90.32% and 75%, respectively. (χ2 = 2.251, P = 0.663). The positive rates of NapsinA in GAS and CCC were 19.36% and 81.25%, respectively. (χ2 = 47.332, P < 0.01). The positive rates of P504S in GAS and CCC were 16.13% and 81.25%, respectively. (χ2 = 41.420, P < 0.01). HNF-1ß was frequently expressed in GAS and CCC, while NapsinA and P504S were frequently expressed in CCC, and reduced or lost in GAS. Conclusion: NapsinA and P504S can be used to differentiate between GAS and CCC.


Assuntos
Adenocarcinoma de Células Claras/genética , Racemases e Epimerases/genética , Neoplasias do Colo do Útero/genética , Neoplasias Uterinas/genética , Adenocarcinoma de Células Claras/enzimologia , Adulto , Biomarcadores Tumorais , Diagnóstico Diferencial , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Imuno-Histoquímica , Neoplasias Gástricas/genética , Neoplasias do Colo do Útero/enzimologia , Neoplasias Uterinas/enzimologia , Útero/patologia , Vagina/patologia
7.
Biochem Biophys Res Commun ; 523(3): 658-665, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31948755

RESUMO

Genome-wide association studies (GWASs) have successfully identified numerous non-coding genetic variants for type 2 diabetes (T2D), but the functional roles underlying these non-coding variants remain largely unknown. The effects of T2D GWAS lead SNPs on transcriptional factors binding motifs were firstly analyzed via JASPAR, followed by functional validations including dual-luciferase reporter assays, biotin-based DNA pull-down assays, real-time quantitative PCR, and western blotting. The results showed that GWAS SNP rs4430796 conferred T allele specific transcriptional enhancer activity via a PAX6 binding element, and upregulated the expression of HNF1B. GWAS SNP rs4607103 showed a bidirectional modulation of ADAMTS9-AS2 and ADAMTS9 by TCF7L2 in a T allele-specific manner. GWAS SNP rs849135 conferred C allele-specific bidirectional transcriptional enhancer activity via a CREB1 binding element. Our findings have uncovered the functional mechanisms of three T2D GWAS SNPs via affecting the binding of transcription factors, providing new insights into the genetics and molecular pathogenesis of T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Proteína ADAMTS9/genética , Proteína ADAMTS9/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Fator 1-beta Nuclear de Hepatócito/genética , Fator 1-beta Nuclear de Hepatócito/metabolismo , Humanos , Fator de Transcrição PAX6/genética , Fator de Transcrição PAX6/metabolismo , Ligação Proteica , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
Nephrol Dial Transplant ; 35(1): 176-183, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31361318

RESUMO

BACKGROUND: Retrospective studies suggest that tacrolimus-induced hypomagnesaemia is a risk factor for post-transplant diabetes mellitus (PTDM), but prospective studies are lacking. METHODS: This was a prospective study with measurements of serum magnesium and tacrolimus at pre-specified time points in the first year after living donor kidney transplantation (KT). The role of single nucleotide polymorphisms (SNPs) in hepatocyte nuclear factor 1ß (HNF1ß) was also explored because HNF1ß regulates insulin secretion and renal magnesium handling. Repeated measurement and regression analyses were used to analyse associations with PTDM. RESULTS: In our cohort, 29 out of 167 kidney transplant recipients developed PTDM after 1 year (17%). Higher tacrolimus concentrations were significantly associated with lower serum magnesium and increased risk of hypomagnesaemia. Patients who developed PTDM had a significantly lower serum magnesium trajectory than patients who did not develop PTDM. In multivariate analysis, lower serum magnesium, age and body mass index were independent risk factors for PTDM. In recipients, the HNF1ß SNP rs752010 G > A significantly increased the risk of PTDM [odds ratio (OR) = 2.56, 95% confidence interval (CI) 1.05-6.23] but not of hypomagnesaemia. This association lost significance after correction for age and sex (OR = 2.24, 95% CI 0.90-5.57). No association between HNF1ß SNPs and PTDM was found in corresponding donors. CONCLUSIONS: A lower serum magnesium in the first year after KT is an independent risk factor for PTDM. The HNF1ß SNP rs752010 G > A may add to this risk through an effect on insulin secretion rather than hypomagnesaemia, but its role requires further confirmation.


Assuntos
Biomarcadores/análise , Diabetes Mellitus/diagnóstico , Fator 1-beta Nuclear de Hepatócito/genética , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Magnésio/sangue , Polimorfismo de Nucleotídeo Único , Diabetes Mellitus/sangue , Diabetes Mellitus/etiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco
9.
Oncogene ; 39(5): 1152-1164, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31570790

RESUMO

Non-small cell lung cancer remains a highly lethal malignancy. Using the tamoxifen inducible Hnf1b:CreERT2 (H) transgenic mouse crossed to the LsL-KrasG12D (K) transgenic mouse, we recently discovered that an Hnf1b positive cell type in the lung is sensitive to adenoma formation when expressing a mutant KrasG12D allele. In these mice, we observe adenoma formation over a time frame of three to six months. To study specificity of the inducible Hnf1b:CreERT2 in the lung, we employed lineage tracing using an mTmG (G) reporter allele. This technique revealed recombined, GFP+ cells were predominantly SPC+. We further employed this technique in HKG mice to determine Hnf1b+ cells give rise to adenomas that express SPC and TTF1. Review of murine lung tissue confirmed a diagnosis of adenoma and early adenocarcinoma, a pathologic subtype of non-small cell lung cancer. Our expanded mouse model revealed loss of Mst1/2 promotes aggressive lung adenocarcinoma and large-scale proteomic analysis revealed upregulation of PKM2 in the lungs of mice with genetic deletion of Mst1/2. PKM2 is a known metabolic regulator in proliferating cells and cancer. Using a human lung adenocarcinoma cell line, we show pharmacologic inhibition of Mst1/2 increases the abundance of PKM2, indicating genetic loss or pharmacologic inhibition of Mst1/2 directly modulates the abundance of PKM2. In conclusion, here we report a novel model of non-small cell lung cancer driven by a mutation in Kras and deletion of Mst1/2 kinases. Tumor development is restricted to a subset of alveolar type II cells expressing Hnf1b. Our data show loss of Mst1/2 regulates levels of a potent metabolic regulator, PKM2.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica , Modelos Animais de Doenças , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas ras/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Deleção de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Hormônios Tireóideos/metabolismo
10.
Oncogene ; 39(6): 1335-1346, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31636385

RESUMO

Prostate cancer is the most common malignancy in men in developed countries. Overexpression of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 methyltransferase, has been connected to prostate cancer malignancy. However, its downstream genes and pathways have not been well established. Here, we show tumor suppressor Hepatocyte Nuclear Factor 1ß (HNF1B) as a direct downstream target of EZH2. EZH2 binds HNF1B locus and suppresses HNF1B expression in prostate cancer cell lines, which is further supported by the reverse correlation between EZH2 and HNF1B expression in clinical samples. Consistently, restored HNF1B expression significantly suppresses EZH2-mediated overgrowth and EMT processes, including migration and invasion of prostate cancer cell lines. Mechanistically, we find that HNF1B primarily binds the promoters of thousands of target genes, and differentially regulates the expression of 876 genes. We also identify RBBP7/RbAP46 as a HNF1B interacting protein which is required for HNF1B-mediated repression of SLUG expression and EMT process. Importantly, we find that higher HNF1B expression strongly predicts better prognosis of prostate cancer, alone or together with lower EZH2 expression. Taken together, we have established a previously underappreciated axis of EZH2-HNF1B-SLUG in prostate cancer, and also provide evidence supporting HNF1B as a potential prognosis marker for metastatic prostate cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/metabolismo , Neoplasias da Próstata/patologia , Fatores de Transcrição da Família Snail/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Masculino , Prognóstico , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Fatores de Transcrição da Família Snail/genética , Células Tumorais Cultivadas
11.
Am J Clin Oncol ; 43(2): 139-145, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31764020

RESUMO

Gynecologic clear cell carcinoma is a rare histology, accounting for ~5% of all ovarian and endometrial cancers in the United States. Compared to other types of gynecologic cancer, they are generally less responsive to standard therapy and have an overall worse prognosis. In addition, mounting evidence suggests that the landscape of genetic and molecular abnormalities observed in these tumors is distinct from other cancers that arise from the same sites of origin. On a molecular level, these tumors characteristically display upregulation of the PI3K-AKT-mTOR and RAS-RAF-MAPK signaling axes, frequent loss of ARID1a, and overexpression of MDM2. Evidence also suggests that these tumors are more likely to express programmed death ligand 1 or demonstrate microsatellite instability than other gynecologic cancers. Despite these important differences, there has been relatively little investigation into histology-specific treatment of clear cell gynecologic cancers, representing an opportunity for new drug development. In this article, we review the unique genetic and molecular features of gynecologic clear cell cancers with an emphasis on potential therapeutic targets. The results of completed studies of treatment for clear cell carcinoma are also presented. We conclude with a discussion of ongoing clinical trials and potential avenues for future study.


Assuntos
Adenocarcinoma de Células Claras/genética , Neoplasias dos Genitais Femininos/genética , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Antineoplásicos Imunológicos/uso terapêutico , Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Fator 1-beta Nuclear de Hepatócito/genética , Fator 1-beta Nuclear de Hepatócito/metabolismo , Humanos , Instabilidade de Microssatélites , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Quinases raf/genética , Quinases raf/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
12.
Proc Natl Acad Sci U S A ; 116(48): 24133-24142, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31712448

RESUMO

Hepatocyte nuclear factor-1ß (HNF-1ß) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1ß produce cystic kidney disease, a phenotype associated with deregulation of canonical (ß-catenin-dependent) Wnt signaling. Here, we show that ablation of HNF-1ß in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including Axin2, Ccdc80, and Rnf43 Levels of ß-catenin and expression of Wnt target genes are also increased in HNF-1ß mutant mouse kidneys. Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) in wild-type and mutant cells showed that ablation of HNF-1ß increases by 6-fold the number of sites on chromatin that are occupied by ß-catenin. Remarkably, 50% of the sites that are occupied by ß-catenin in HNF-1ß mutant cells colocalize with HNF-1ß-occupied sites in wild-type cells, indicating widespread reciprocal binding. We found that the Wnt target genes Ccdc80 and Rnf43 contain a composite DNA element comprising a ß-catenin/lymphoid enhancer binding factor (LEF) site overlapping with an HNF-1ß half-site. HNF-1ß and ß-catenin/LEF compete for binding to this element, and thereby HNF-1ß inhibits ß-catenin-dependent transcription. Collectively, these studies reveal a mechanism whereby a transcription factor constrains canonical Wnt signaling through direct inhibition of ß-catenin/LEF chromatin binding.


Assuntos
Fator 1-beta Nuclear de Hepatócito/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Linhagem Celular , Elementos Facilitadores Genéticos , Células Epiteliais/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Fator 1-beta Nuclear de Hepatócito/genética , Medula Renal/citologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Mutação , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo
13.
Ren Fail ; 41(1): 832-841, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31509055

RESUMO

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.


Assuntos
Genes Dominantes , Falência Renal Crônica/genética , Túbulos Renais/patologia , Adulto , Idoso , Estudos Transversais , Feminino , Testes Genéticos/estatística & dados numéricos , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Irlanda/epidemiologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Mucina-1/genética , Mutação , Prevalência , Uromodulina/genética
14.
BMC Nephrol ; 20(1): 353, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500578

RESUMO

BACKGROUND: 17q12 deletion syndrome encompasses a broad constellation of clinical phenotypes, including renal magnesium wasting, maturity-onset diabetes of the young (MODY), renal cysts, genitourinary malformations, and neuropsychiatric illness. Manifestations outside of the renal, endocrine, and nervous systems have not been well described. CASE PRESENTATION: We report a 62-year-old male referred to the Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH) who presented with persistent hypermagnesiuric hypomagnesemia and was found to have a 17q12 deletion. The patient exhibited several known manifestations of the syndrome, including severe hypomagnesemia, renal cysts, diabetes and cognitive deficits. Coronary CT revealed extensive coronary calcifications, with a coronary artery calcification score of 12,427. Vascular calcifications have not been previously reported in this condition. We describe several physiologic mechanisms and a review of literature to support the expansion of the 17q12 deletion syndrome to include vascular calcification. CONCLUSION: Extensive coronary and vascular calcifications may be an extension of the 17q12 deletion phenotype, particularly if hypomagnesemia and hyperparathyroidism are prevalent. In patients with 17q12 deletions involving HNF1B, hyperparathyroidism and hypomagnesemia may contribute to significant cardiovascular risk.


Assuntos
Doença das Coronárias/genética , Fator 1-beta Nuclear de Hepatócito/genética , Erros Inatos do Transporte Tubular Renal/genética , Síndrome de Smith-Magenis/genética , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Erros Inatos do Transporte Tubular Renal/complicações , Erros Inatos do Transporte Tubular Renal/diagnóstico por imagem , Síndrome de Smith-Magenis/complicações , Síndrome de Smith-Magenis/diagnóstico por imagem
15.
Prenat Diagn ; 39(12): 1136-1147, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31498910

RESUMO

OBJECTIVE: 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. METHODS: Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. RESULTS: In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. CONCLUSIONS: We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/diagnóstico , Análise em Microsséries , Diagnóstico Pré-Natal/métodos , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Criança , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Estudos de Coortes , Hibridização Genômica Comparativa/métodos , Análise Mutacional de DNA/métodos , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , Doenças Renais Císticas/genética , Masculino , Análise em Microsséries/métodos , Mutação , Gravidez , Síndrome
16.
EMBO J ; 38(20): e102161, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31531882

RESUMO

Differentiation of normal and tumor cells is controlled by regulatory networks enforced by lineage-determining transcription factors (TFs). Among them, TFs such as FOXA1/2 bind naïve chromatin and induce its accessibility, thus establishing new gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of well- and poorly differentiated cells at all stages of disease. How the transcriptional networks determining such massive cellular heterogeneity are established remains to be determined. We found that FOXA2, a TF controlling pancreas specification, broadly contributed to the cis-regulatory networks of PDACs. Despite being expressed in both well- and poorly differentiated PDAC cells, FOXA2 displayed extensively different genomic distributions and controlled distinct gene expression programs. Grade-specific functions of FOXA2 depended on its partnership with TFs whose expression varied depending on the differentiation grade. These data suggest that FOXA2 contributes to the regulatory networks of heterogeneous PDAC cells via interactions with alternative partner TFs.


Assuntos
Diferenciação Celular , Regulação Neoplásica da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias Pancreáticas/patologia , Elementos Reguladores de Transcrição , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Movimento Celular , Proliferação de Células , Redes Reguladoras de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Humanos , Gradação de Tumores , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Células Tumorais Cultivadas
17.
Endocr J ; 66(12): 1113-1116, 2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31391355

RESUMO

We report a sporadic case of maturity-onset diabetes of the young type 5 (MODY5) with a whole-gene deletion of the hepatocyte nuclear factor-1beta (HNF1B) gene. A 44-year-old Japanese man who had been diagnosed with early-onset non-autoimmune diabetes mellitus at the age of 23 was examined. He showed multi-systemic symptoms, including a solitary congenital kidney, pancreatic hypoplasia, pancreatic exocrine dysfunction, elevation of the serum levels of liver enzymes, hypomagnesemia, and hyperuricemia. These clinical characteristics, in spite of the absence of a family history of diabetes, prompted us to make the diagnosis of maturity-onset diabetes of the young 5 (MODY 5). One allele deletion of the entire HNF1B gene revealed by multiplex ligation-dependent probe amplification (MLPA) led us to the diagnoses of 17q12 microdeletion syndrome even though there were negative chromosomal analyses with array comparative genomic hybridization (CGH). 17q12 microdeletion syndrome, which is not rare especially in sporadic cases since 17q12 is a typical hot spot for chromosomal deletion, could have complicated the clinical heterogeneity of MODY5.


Assuntos
Cromossomos Humanos Par 17/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Deleção de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Adulto , Cálcio/urina , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Japão , Fígado/enzimologia , Magnésio/sangue , Masculino , Pâncreas/fisiopatologia , Síndrome , Tomografia Computadorizada por Raios X
18.
Cell Mol Gastroenterol Hepatol ; 8(3): 487-511, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31229598

RESUMO

BACKGROUND & AIMS: The exocrine pancreas consists of acinar cells that produce digestive enzymes transported to the intestine through a branched ductal epithelium. Chronic pancreatitis is characterized by progressive inflammation, fibrosis, and loss of acinar tissue. These changes of the exocrine tissue are risk factors for pancreatic cancer. The cause of chronic pancreatitis cannot be identified in one quarter of patients. Here, we investigated how duct dysfunction could contribute to pancreatitis development. METHODS: The transcription factor Hnf1b, first expressed in pancreatic progenitors, is strictly restricted to ductal cells from late embryogenesis. We previously showed that Hnf1b is crucial for pancreas morphogenesis but its postnatal role still remains unelucidated. To investigate the role of pancreatic ducts in exocrine homeostasis, we inactivated the Hnf1b gene in vivo in mouse ductal cells. RESULTS: We uncovered that postnatal Hnf1b inactivation in pancreatic ducts leads to chronic pancreatitis in adults. Hnf1bΔduct mutants show dilatation of ducts, loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis. We deciphered the early events involved, with down-regulation of cystic disease-associated genes, loss of primary cilia, up-regulation of signaling pathways, especially the Yap pathway, which is involved in acinar-to-ductal metaplasia. Remarkably, Hnf1bΔduct mutants developed pancreatic intraepithelial neoplasia and promote pancreatic intraepithelial neoplasia progression in concert with KRAS. We further showed that adult Hnf1b inactivation in pancreatic ducts is associated with impaired regeneration after injury, with persistent metaplasia and initiation of neoplasia. CONCLUSIONS: Loss of Hnf1b in ductal cells leads to chronic pancreatitis and neoplasia. This study shows that Hnf1b deficiency may contribute to diseases of the exocrine pancreas and gains further insight into the etiology of pancreatitis and tumorigenesis.


Assuntos
Carcinoma in Situ/genética , Deleção de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Ductos Pancreáticos/crescimento & desenvolvimento , Neoplasias Pancreáticas/genética , Pancreatite/genética , Animais , Animais Recém-Nascidos , Carcinoma in Situ/metabolismo , Feminino , Predisposição Genética para Doença , Fator 1-beta Nuclear de Hepatócito/metabolismo , Homeostase , Humanos , Camundongos , Pâncreas Exócrino/metabolismo , Ductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatite/complicações , Pancreatite/metabolismo , Transdução de Sinais
19.
Am J Physiol Renal Physiol ; 317(2): F478-F488, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31188030

RESUMO

The hepatocyte nuclear factor-1ß (Hnf1b) transcription factor is a key regulator of kidney tubule formation and is associated with a syndrome of renal cysts and early onset diabetes. To further our understanding of Hnf1b in the developing zebrafish kidney, we performed RNA sequencing analysis of proximal tubules from hnf1b-deficient larvae. This analysis revealed an enrichment of gene transcripts encoding transporters of the solute carrier (SLC) superfamily, including multiple members of slc2 and slc5 glucose transporters. An investigation of expression of slc2a1a, slc2a2, and slc5a2 as well as a poorly studied glucose/mannose transporter encoded by slc5a9 revealed that these genes undergo dynamic spatiotemporal changes during tubule formation and maturation. A comparative analysis of zebrafish SLC genes with those expressed in mouse proximal tubules showed a substantial overlap at the level of gene families, indicating a high degree of functional conservation between zebrafish and mammalian proximal tubules. Taken together, our findings are consistent with a role for Hnf1b as a critical determinant of proximal tubule transport function by acting upstream of a large number of SLC genes and validate the zebrafish as a physiologically relevant model of the mammalian proximal tubule.


Assuntos
Perfilação da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/genética , Fator 1-beta Nuclear de Hepatócito/fisiologia , Túbulos Renais Proximais/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Larva , Camundongos , RNA/biossíntese , RNA/genética , Especificidade da Espécie
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA