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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
In Vitro Cell Dev Biol Anim ; 55(7): 512-521, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144266

RESUMO

Hepatocyte nuclear factor-1ß (Hnf1ß) is associated with early embryogenesis failure, renal cysts, and/or diabetes. However, factors regulating Hnf1ß expression in metanephric mesenchyme cells remain poorly understood. Here, we analyzed the modulation relationship of Hnf1ß and miR-194 in mouse metanephric mesenchyme (MM) cells. Bioinformatics analysis, luciferase assay and semi-quantitative real-time (qPCR), western blotting, 5-ethynyl-2'-deoxyuridine cell proliferation assay, wound healing assay, and flow cytometry were employed to detect the function of miR-194 by targeting on Hnf1ß in mouse MM cells. Bioinformatic prediction revealed one conserved binding site (CAGTATT) of miR-194 on Hnf1ß 3'-UTR and luciferase reporter assay suggested that this is an effective target site of miR-194, and mutating CAGTATT with CGTACTT had no effects on luciferase activity compared with control. Overexpression of miR-194 decreased Hnf1ß mRNA and protein level in mouse MM cells. In addition, miR-194-decreased cell proliferation and miR-194-promoted cell apoptosis and migration were reversed by overexpression of Hnf1ß coding region. In addition, Hnf1ß-upregulated genes were decreased in miR-194 overexpression cells and rescued in miR-194 and Hnf1ß CDS region co-overexpression cells. Our findings explored one new regulator of Hnf1ß and revealed the function of their regulation in cell proliferation, migration, and apoptosis in mouse metanephric mesenchyme cells. For strict regulation of Hnf1ß in kidney development, these findings provide theoretical guidance for kidney development study and kidney disease therapy.


Assuntos
Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Fator 1-beta Nuclear de Hepatócito/genética , Rim/embriologia , MicroRNAs/genética , Animais , Sítios de Ligação/genética , Linhagem Celular , Células HEK293 , Humanos , Rim/metabolismo , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Ativação Transcricional
8.
Clin Exp Nephrol ; 23(9): 1119-1129, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31131422

RESUMO

BACKGROUND: Hepatocyte nuclear factor 1ß (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.


Assuntos
Síndrome de Bartter/genética , Doenças do Sistema Nervoso Central/genética , Deleção Cromossômica , Cromossomos Humanos Par 17 , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/genética , Deleção de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Adolescente , Adulto , Síndrome de Bartter/diagnóstico , Doenças do Sistema Nervoso Central/diagnóstico , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Diabetes Mellitus Tipo 2/diagnóstico , Progressão da Doença , Predisposição Genética para Doença , Hereditariedade , Humanos , Lactente , Japão , Doenças Renais Císticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Linhagem , Fenótipo , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Anormalidades Urogenitais/diagnóstico , Refluxo Vesicoureteral/diagnóstico
9.
Arch Endocrinol Metab ; 63(3): 250-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31066763

RESUMO

OBJECTIVE: To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. SUBJECTS AND METHODS: We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. RESULTS: We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. CONCLUSION: The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).


Assuntos
Nefropatias Diabéticas/genética , Fator 1-beta Nuclear de Hepatócito/genética , Hiperglicemia/genética , Doenças Renais Císticas/genética , Mutação , Adulto , Brasil , Estudos de Coortes , Nefropatias Diabéticas/complicações , Deleção de Genes , Humanos , Hiperglicemia/complicações , Doenças Renais Císticas/complicações , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético/genética
10.
Biosci Biotechnol Biochem ; 83(11): 2008-2015, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31038395

RESUMO

Hepatocyte nuclear factor 1ß (HNF1ß) is a transcription factor belonging to the HNF-1 family and has been implicated in a number of cancers, but its role in Wilms' tumor (nephroblastoma) has not been addressed. Here, we compared its expression between Wilms' tumor patient kidney tissue and adjacent tissue based on the Oncomine database ( www.oncomine.com ). Cell proliferation, apoptosis, migration, and HNF1ß expression level were analyzed in Wilms' tumor-derived G401 cells. Using a variety of mouse tissues (lung, heart, kidney, etc.), we found that HNF1ß is the highest expression in the kidneys. Oncomine analysis further demonstrated that HNF1ß has a lower expression in Wilms' tumor tissue than in paracancerous tissues. Overexpression of HNF1ß decreased cell proliferation and migration, but promoted cell apoptosis. Knockdown of HNF1ß produced the opposite results. These results indicated that HNF1ß may play important roles in kidney development and function, and its activation may negatively regulate Wilms' tumor progression.


Assuntos
Fator 1-beta Nuclear de Hepatócito/metabolismo , Neoplasias Renais/metabolismo , Tumor de Wilms/metabolismo , Carcinogênese , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Transdução de Sinais , Tumor de Wilms/genética , Tumor de Wilms/patologia
11.
J Diabetes Investig ; 10(6): 1590-1592, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30860651

RESUMO

We report a case of missed diagnosis of maturity-onset diabetes of the young type 5 uncovered during pregnancy with a previous diagnosis of type 1 diabetes. Maturity-onset diabetes of the young type 5 cannot be excluded in early-onset diabetes with positive islet-related autoantibodies and type 1 diabetes-prone human leukocyte antigen subtypes. Abdominal ultrasound should be used in all patients with pre-gestational diabetes, and maturity-onset diabetes of the young type 5 should be considered when renal abnormality is presented.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Glutamato Descarboxilase/imunologia , Adulto , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diagnóstico Diferencial , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Mutação , Gravidez , Prognóstico
12.
Ital J Pediatr ; 45(1): 27, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791938

RESUMO

BACKGROUND: paucity of interlobular bile ducts is an important observation at liver biopsy in the diagnostic work-up of neonatal cholestasis. To date, other than in the Alagille syndrome, syndromic paucity of interlobular bile ducts has been documented in four cholestatic neonates with HFN1ß mutations. A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. This is usually characterized by a wide clinical spectrum, including renal cysts, maturity-onset diabetes of the young, exocrine pancreatic insufficiency, urogenital abnormalities and a not well established liver involvement. Herein we report a novel case of paucity of interlobular bile ducts due to an HFN1ß defect. CASE PRESENTATION: A 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks' gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1ß gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control. CONCLUSIONS: Alagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1ß deficiency should also be ruled out, taking into consideration HNF1ß mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.


Assuntos
Síndrome de Alagille/diagnóstico , Colestase Intra-Hepática/etiologia , Fator 1-beta Nuclear de Hepatócito/deficiência , Síndrome de Alagille/complicações , Humanos , Lactente , Masculino
13.
J Diabetes Investig ; 10(4): 1112-1115, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30637974

RESUMO

Here, we report phenotypic differences and similarities of monozygotic twins with maturity-onset diabetes of the young type 5 harboring a partial deletion of chromosome 17q12. The proband and her twin sister manifested complete aplasia and marked hypoplasia, respectively, of the body and tail of the pancreas. Whereas both twins showed marked hypoplasia of the right kidney and multiple cysts in both kidneys, only the proband's sister showed hydronephrosis in the left kidney. The proband had profound defects in insulin and glucagon secretion, as well as mild renal dysfunction, whereas her sister had pronounced renal dysfunction accompanied by mild defects in insulin and glucagon secretion. Both twins manifested hypomagnesemia and hyperuricemia, but no apparent liver dysfunction or intellectual disability. The severity of renal and pancreatic defects differed between monozygotic twins with maturity-onset diabetes of the young type 5, suggesting that the phenotypes of this condition are determined not solely by genetic factors.


Assuntos
Biomarcadores/análise , Doenças do Sistema Nervoso Central/fisiopatologia , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/fisiopatologia , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/fisiopatologia , Nefropatias/diagnóstico , Pancreatopatias/diagnóstico , Adulto , Esmalte Dentário/fisiopatologia , Feminino , Deleção de Genes , Humanos , Incidência , Secreção de Insulina , Nefropatias/epidemiologia , Pancreatopatias/epidemiologia , Fenótipo , Gêmeos Monozigóticos
14.
Pediatr Nephrol ; 34(6): 1065-1075, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30666461

RESUMO

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.


Assuntos
Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/patologia , Doenças Renais Policísticas/fisiopatologia , Adolescente , Idade de Início , Criança , Pré-Escolar , Progressão da Doença , Feminino , Estudos de Associação Genética , Alemanha , Humanos , Lactente , Recém-Nascido , Falência Renal Crônica/genética , Masculino , Fenótipo , Sistema de Registros
15.
Am J Surg Pathol ; 43(3): 325-333, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30608233

RESUMO

BACKGROUND: The Arias-Stella reaction (ASR) can mimic endometrial clear cell carcinoma (ECCC) in small biopsies, especially when drug or pregnancy history is unknown. A panel of immunohistochemical markers comprising napsin A, hepatocyte nuclear factor-1-beta (HNF-1ß), estrogen and progesterone receptors (ER, PR) has been found useful in confirming a diagnosis of ECCC. However, the detailed characterization of how expression of this combination of markers in the ECCC mimics ASR has yet to be thoroughly evaluated. DESIGN: The frequency and extent of napsin A, HNF-1ß, ER, and PR expression in ASR were assessed in a large series. For napsin A, any cytoplasmic staining was considered positive while only nuclear staining was deemed to be positive for HNF-1ß, ER, and PR. Immunohistochemical histoscores based on the intensity and extent of staining were calculated. RESULTS: Forty cases were gestational and 10 were nongestational ASR. In 19 (38%), the reaction was extensive and involved >50% of the glands. A stromal decidual change was found in 31 (77.5%) of the gestational and 3 (30%) of the nongestational cases. Napsin A was positive in all gestational and 8 of 10 (80%) nongestational ASR. All ASR showed HNF-1ß expression. ER expression was reduced in 37 (92.5%) and lost in 3 (7.5%) gestational ASR, and reduced in 9 (90%) and lost in 1 (10%) of nongestational ASR. None of the ASR in our series expressed PR. CONCLUSIONS: Naspin A and HNF-1ß were frequently expressed in both gestational and nongestational ASR, and ER expression was usually either reduced or loss. Interpretation of these markers in small biopsies containing atypical clear cells should be made with caution.


Assuntos
Adenocarcinoma de Células Claras/diagnóstico , Biomarcadores Tumorais/análise , Neoplasias do Endométrio/diagnóstico , Doenças Uterinas/diagnóstico , Adolescente , Adulto , Ácido Aspártico Endopeptidases/análise , Ácido Aspártico Endopeptidases/biossíntese , Diagnóstico Diferencial , Feminino , Fator 1-beta Nuclear de Hepatócito/análise , Fator 1-beta Nuclear de Hepatócito/biossíntese , Humanos , Gravidez , Receptores Estrogênicos/análise , Receptores Estrogênicos/biossíntese , Receptores de Progesterona/análise , Receptores de Progesterona/biossíntese , Adulto Jovem
17.
Oncol Rep ; 41(3): 1729-1738, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30592289

RESUMO

In the present study, we summarize the role of the shared and independent (epi)genetic background between endometrioid carcinoma (EC) and clear cell carcinoma (CCC), two histological subtypes of endometriosis-associated ovarian cancer (EAOC). Using the PubMed database, we conducted a literature review of various studies related to the malignant transformation of endometriosis. Both endometriosis and EAOC face potential environmental hazards, including hemoglobin (Hb), heme and free iron, which induces DNA damage and mutations. Although EC is distinguished from CCC due to different morphologies, both represent common environmental profiles and maintain the similar (epi)genomic abnormalities with multiple overlaps and share similar molecular signatures. By contrast, EAOC also has disease-specific gene signatures corresponding with each histological subtype: Estrogen receptor promotes EC cell proliferation ('go') and hepatocyte nuclear factor-1ß (HNF-1ß) induces CCC cell cycle arrest ('stop') under oxidative stress conditions. This model underscores a subtype-dependent 'go or stop' dichotomy, possibly through better ability to adapt in a changing environment. It was found that cyst fluid Hb and iron concentrations were significantly lower in EAOC when compared to benign ovarian endometrioma (OE), supporting the hypothesis that the redox imbalance plays a key role in the pathogenesis of EAOC. There are at least two phases of iron carcinogenesis and tumor progression: The initial wave of iron-induced oxidative stress and DNA mutations would be followed by the second big wave of subsequent synthesis of the antioxidants, which diminishes cellular oxidative stress capacity, increases apoptosis resistance and promotes tumor initiation and progression. Special emphasis is given to novel pathophysiological concepts of malignant transformation of endometriosis.


Assuntos
Adenocarcinoma de Células Claras/patologia , Carcinoma Endometrioide/patologia , Transformação Celular Neoplásica/genética , Endometriose/patologia , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/genética , Animais , Carcinoma Endometrioide/genética , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Endometriose/genética , Epigênese Genética , Feminino , Fator 1-beta Nuclear de Hepatócito/metabolismo , Humanos , Ferro/toxicidade , Mutação , Neoplasias Ovarianas/genética , Estresse Oxidativo , Receptores Estrogênicos/metabolismo
18.
Int J Gynecol Pathol ; 38(3): 276-282, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29901522

RESUMO

The incidence of cervical adenocarcinoma, both absolute and relative to squamous cell carcinoma, is increasing. Most cervical adenocarcinomas are human papillomavirus associated, although non-human papillomavirus-associated neoplasms exist; the latter include gastric-type adenocarcinoma (GAS) and clear cell carcinoma (CCC). Histologically, these 2 tumors may superficially resemble one other and although morphologic evaluation usually permits a correct diagnosis, immunohistochemistry may be required to resolve diagnostic uncertainty, especially in a small biopsy specimen. Markers of CCC include hepatocyte nuclear factor 1 beta (HNF1ß) and Napsin A. In order to explore the utility of these markers in distinguishing between GAS and CCC, we stained 24 cases of GAS (19 cervical, 5 vaginal), 3 of cervical gastric-type adenocarcinoma in situ (gAIS) and 14 CCCs (13 cervical, 1 vaginal) with these antibodies. We found HNF1ß expression in 21 of 23 cases of GAS (91.3%; there was no material available for staining in 1 case), 3/3 cases of gAIS (100%) and 10 of 14 (71.4%) CCCs. Napsin A was expressed in 4 of 24 (16.7%) cases of GAS, 0 of 3 (0%) gAIS, and 11 of 14 (78.6%) CCC. On the basis of these findings, Napsin A is of value in resolving diagnostic confusion between GAS and CCC, whereas HNF1ß lacks specificity and its use in this setting is discouraged.


Assuntos
Adenocarcinoma de Células Claras/diagnóstico , Ácido Aspártico Endopeptidases/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Gástricas/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias Vaginais/diagnóstico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Colo do Útero/metabolismo , Colo do Útero/patologia , Diagnóstico Diferencial , Feminino , Fator 1-beta Nuclear de Hepatócito/metabolismo , Humanos , Imuno-Histoquímica , Sensibilidade e Especificidade , Neoplasias do Colo do Útero/metabolismo , Vagina/metabolismo , Vagina/patologia , Neoplasias Vaginais/metabolismo , Neoplasias Vaginais/patologia
19.
Appl Immunohistochem Mol Morphol ; 27(4): e32-e38, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29406331

RESUMO

Biliary atresia (BA) is a necroinflammatory occlusive cholangiopathy that affects infants. Genetic and environmental factors has been proposed for its occurrence. The objectives of this study was to investigate the protein expression of 2 important genes regulating ductal plate remodeling, hepatocyte nuclear factor 1-beta (Hnf1ß) and the fork head box protein A2 (FoxA2) in liver tissue from patients with BA and to compare their expression with other causes of neonatal cholestasis (NC). This retrospective study included 60 pediatric patients, 30 with BA and 30 with NC. Immunohistochemistry of Hnf1ß and FoxA2 was performed on liver tissues from studied patients as well as 20 healthy subjects. Statistical analysis between immunohistochemistry results and other parameters was performed. Liver tissue from patients with BA revealed reduced Hnf1ß and FoxA2 immunoexpression. A strong significant statistical difference between BA and NC group (P<0.0001) with regard to Hnf1ß and FoxA2 immunoexpression was evident. Moreover, Hnf1ß was significantly correlated with FoxA2 immunoexpression, stage of fibrosis, bile ductular proliferation, and bile plugs in bile ductules. Hnf1ß immunoreaction in BA cases showed 76.7% sensitivity, 90% specificity, 88.5% positive predictive value, 79.4% negative predictive value, and 83.4% accuracy. FoxA2 expression in BA cases revealed 70.0% sensitivity, 80.0% specificity, 77.8% positive predictive value, 72.7% negative predictive value, 75.0% accuracy. Hnf1ß and FoxA2 immunoexpression could differentiate between BA from other cause of NC.


Assuntos
Atresia Biliar , Colestase , Regulação da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/biossíntese , Fator 3-beta Nuclear de Hepatócito/biossíntese , Fígado , Atresia Biliar/metabolismo , Atresia Biliar/patologia , Colestase/metabolismo , Colestase/patologia , Feminino , Humanos , Imuno-Histoquímica , Lactente , Fígado/metabolismo , Fígado/patologia , Masculino , Estudos Retrospectivos
20.
Med Clin (Barc) ; 152(1): 19-21, 2019 01 04.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29525113

RESUMO

INTRODUCTION: MODY diabetes encompasses heterogeneous group of monogenic forms of diabetes with low prevalence. It is not easily diagnosed because of the increase in obesity and family history of diabetes in the general population. PATIENTS AND METHODS: We present a clinical case with cardinal symptoms, diabetes,renal insufficiency with no acidosis and with a family history of diabetes and renal agenesis. RESULTS: Distinguishing MODY diabetes from DM1 and DM2 is very important to ensure optimal treatment, and because the risk of complications depends on each genetic defect. A proper diagnosis needs a detailed medical history. DISCUSSION: An earlier identification of family members at risk and a correct and individualised treatment could be possible. Many of these patients can be managed successfully in monotherapy without insulin therapy.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Rim Único/complicações , Adulto , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diagnóstico Diferencial , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Masculino , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia
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