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1.
Rev. neurol. (Ed. impr.) ; 71(10): 375-376, 16 nov., 2020. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-ET6-1308

RESUMO

INTRODUCCIÓN: La leucoencefalopatía megalencefálica con quistes es una leucodistrofia de origen genético que produce una alteración de la homeostasis del agua e iones en el cerebro, generando formas vacuolares y edema crónico en la sustancia blanca con deterioro neurológico progresivo. Debe sospecharse en los lactantes que presentan macrocefalia progresiva durante el primer año de vida, retraso motor y hallazgos característicos en la resonancia magnética cerebral. CASO CLÍNICO: Niña en seguimiento desde los 9 meses por macrocefalia progresiva y retraso del desarrollo psicomotor con presencia en la resonancia magnética cerebral de hallazgos compatibles con leucoencefalopatía megalencefálica con quistes, y aparición de epilepsia en su evolución. Los estudios genéticos habituales (secuenciación de nueva generación y array) fueron negativos, pero, al cumplir los criterios diagnósticos, se procedió al estudio del ARN mensajero y el ADN complementario, que confirmó la presencia de dos variantes patogénicas en MLC1. CONCLUSIONES: La leucoencefalopatía megalencefálica con quistes es una entidad infrecuente. Es característica la macrocefalia progresiva en el primer año de vida, la ausencia de deterioro o deterioro lento, y la posibilidad de desarrollar epilepsia, espasticidad y ataxia en su evolución. Cobra importancia en dichos pacientes la realización de una prueba de imagen que muestre hallazgos propios de la entidad, lo que, junto con la clínica, permite diferenciarla de otras leucodistrofias y establecer un diagnóstico confirmatorio. Los estudios genéticos pueden constatar la mutación asociada que posibilita predecir el fenotipo clinicorradiológico


INTRODUCTION: Megalencephalic leukoencephalopathy with cysts is a leukodystrophy of genetic origin that produces an alteration in the water and ion homeostasis in the brain, generating vacuolar forms and chronic oedema in the white matter with progressive neurological deterioration. It should be suspected in infants who present progressive macrocephaly during the first year of life, motor retardation and characteristic findings in magnetic resonance brain scans. CASE REPORT: We report the case of a girl who was followed up from the age of 9 months due to progressive macrocephaly and delayed psychomotor development and brain MRI findings consistent with megalencephalic leukoencephalopathy with cysts, and the appearance of epilepsy during its development. The usual genetic studies (new generation sequencing and array) were negative, but as the diagnostic criteria were met, a complementary messenger RNA and DNA study was conducted, which confirmed the presence of two pathogenic variants in MLC1. CONCLUSIONS: Megalencephalic leukoencephalopathy with cysts is a rare condition. Progressive macrocephaly in the first year of life, the absence of deterioration or slow deterioration, and the possibility of developing epilepsy, spasticity and ataxia are characteristic signs in its course. It is important for these patients to undergo an imaging test that shows findings that characterise this condition, which, together with the clinical features, makes it possible to differentiate it from other leukodystrophies and to establish a confirmatory diagnosis. Genetic studies can confirm the associated mutation that makes it possible to predict the clinicoradiological phenotype


Assuntos
Humanos , Feminino , Lactente , Cistos/diagnóstico , Cistos/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Imagem por Ressonância Magnética , Proteínas de Membrana/genética , Proteínas de Ciclo Celular/genética , Mutação
2.
Nat Commun ; 11(1): 4320, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859916

RESUMO

In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl- secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca2+ signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca2+ signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.


Assuntos
Anoctamina-1/genética , Anoctamina-1/metabolismo , Cistos/metabolismo , Rim Policístico Autossômico Dominante/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo , Animais , Anoctamina-1/efeitos dos fármacos , Benzobromarona/farmacologia , Canais de Cálcio , Proliferação de Células , Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística , Cistos/tratamento farmacológico , Cistos/genética , Modelos Animais de Doenças , Cães , Células Epiteliais/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Néfrons/metabolismo , Niclosamida/farmacologia , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética
3.
BMC Psychiatry ; 20(1): 349, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620087

RESUMO

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC), or Van der Knaap disease, is a rare spongiform leukodystrophy that is characterized by macrocephaly, progressive motor dysfunction, and mild mental retardation. It is very rare for mental illness such as psychotic disorders, affective disorders and anxiety disorders to occur in MLC. CASE PRESENTATION: A 17-year-old boy was admitted to our hospital after he developed symptoms of depressive state with catatonia after being diagnosed as having MLC with confirmed MLC1 mutation. His catatonic symptoms were improved with administration of olanzapine and sertraline and he was discharged after 4 months. Several months later, he became hypomanic. He was diagnosed with bipolar II disorder. Mood swings were controlled with the administration of carbamazepine. CONCLUSIONS: This case is the first report of bipolar disorder during the clinical course of MLC. This case indicate the possibility that MLC influences the development of bipolar disorder in MLC, however, further studies involving more patients are required to clarify this.


Assuntos
Transtorno Bipolar/diagnóstico , Encéfalo/diagnóstico por imagem , Catatonia/complicações , Cistos , Depressão/complicações , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Adolescente , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Catatonia/diagnóstico , Cistos/diagnóstico , Cistos/genética , Depressão/diagnóstico , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Imagem por Ressonância Magnética , Megalencefalia
4.
Am J Hum Genet ; 106(5): 694-706, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32359472

RESUMO

How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcifications and cysts (LCC) is poorly understood. Here, we report the generation of a mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development, a disturbance of ribosomal RNA (rRNA) biogenesis and tp53 activation, which monitors ribosome biogenesis. Further, we demonstrate that fibroblasts from individuals with LCC are defective in rRNA processing. Human precursor-U8 (pre-U8) containing a 3' extension rescued mutant U8 zebrafish, and this result indicates conserved biological function. Analysis of LCC-associated U8 mutations in zebrafish revealed that one null and one functional allele contribute to LCC. We show that mutations in three nucleotides at the 5' end of pre-U8 alter the processing of the 3' extension, and we identify a previously unknown base-pairing interaction between the 5' end and the 3' extension of human pre-U8. Indeed, LCC-associated mutations in any one of seven nucleotides in the 5' end and 3' extension alter the processing of pre-U8, and these mutations are present on a single allele in almost all individuals with LCC identified to date. Given genetic data indicating that bi-allelic null U8 alleles are likely incompatible with human development, and that LCC is not caused by haploinsufficiency, the identification of hypomorphic misprocessing mutations that mediate viable embryogenesis furthers our understanding of LCC molecular pathology and cerebral vascular homeostasis.


Assuntos
Alelos , Calcinose/genética , Cistos do Sistema Nervoso Central/genética , Cistos/genética , Leucoencefalopatias/genética , Mutação , RNA Nucleolar Pequeno/genética , Peixe-Zebra/genética , Animais , Sequência de Bases , Calcinose/patologia , Cistos do Sistema Nervoso Central/patologia , Sequência Conservada , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Humanos , Leucoencefalopatias/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 543-546, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335882

RESUMO

OBJECTIVE: To explore the clinical features and genetic variant in a child featuring megalencephalic leukoencephalopathy with subcortical cyst (MLC) type 2B. METHODS: Clinical and imaging data of the child was collected. Potential variant of hepatocyte adhesion molecule (HEPACAM) gene was detected by Sanger sequencing. The growth and development of her mother and uncle was also reviewed. RESULTS: The patient, a 1-year-and-7-month female, presented with convulsion, mental retardation and abnormally increased head circumference. Cranial MRI revealed extensive long T1 long T2 signals in the white matter of bilateral cerebral hemisphere, right anterior sac cyst, cerebral gyrus widening, and shallow sulcus. Sanger sequencing identified a c.437C>T missense variant in exon 3 of the HEPACAM gene. The same variant was detected in her mother but not father. Her mother and maternal uncle both had a history of increased head circumference when they were young. In their adulthood, the head circumference was in the normal range but still greater than the average. CONCLUSION: The heterozygous variant of the HEPACAM gene probably underlies the MLC2B in this child. The variant has derived from her asymptomatic mother, which suggested incomplete penetrance of the MLC2B.


Assuntos
Proteínas de Ciclo Celular , Cistos , Variação Genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Adulto , Proteínas de Ciclo Celular/genética , Cérebro/diagnóstico por imagem , Cistos/diagnóstico por imagem , Cistos/genética , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Lactente
6.
J Thorac Cardiovasc Surg ; 159(4): 1214-1220.e1, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905418

RESUMO

OBJECTIVES: This study aimed to review the clinical results of young adult patients with aortic disease associated with mutations in the fibrillin-1 gene (FBN1) and disclose the histologic differences between the ascending and descending aortas. METHODS: Between 2012 and 2015, 94 patients aged less than 50 years underwent surgery for thoracic aortic diseases. Forty-two patients (44.7%) had FBN-1 mutations. Of these, 40 patients (42.5%) with surgical specimens for histologic evaluation were included in the study. With the histologic results including the specimen sampled at their previous operations, cystic medial necrosis was classified into 3 grades according to the degree of the cystic area. RESULTS: Thirty-nine patients (97.5%) had aortic root dilatation (Z ≥2), and 13 patients (32.5%) had ectopia lentis. Thirty-nine patients (97.5%) fulfilled the diagnostic criteria for Marfan syndrome. There were no in-hospital deaths. The majority (27/29: 93.1%) of the specimens of the ascending aorta revealed cystic medial necrosis pattern. With grade III being the most severe condition, these cases were classified into grade I (n = 2), grade II (n = 5), and grade III (n = 20). In contrast, only 6 specimens (6/17: 35.3%) of the descending aorta showed a cystic medial necrosis pattern that was classified into grade I (n = 2) and grade III (n = 4), (P < .00001). CONCLUSIONS: Fewer specimens of the descending aorta revealed cystic medial necrosis compared with those of the ascending aorta. This difference might influence the characteristic aortic disease in Marfan syndrome associated with FBN-1 mutations.


Assuntos
Aorta Abdominal/patologia , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Cistos/genética , Cistos/patologia , Fibrilina-1/genética , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Adulto , Ectopia do Cristalino/genética , Ectopia do Cristalino/patologia , Feminino , Humanos , Masculino , Síndrome de Marfan/cirurgia , Pessoa de Meia-Idade , Mutação
7.
Clin Dysmorphol ; 29(1): 24-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30946036

RESUMO

Microdeletion of the entire interferon regulatory factory 6 (IRF 6) gene is a rare cause of Van der Woude syndrome (VDW) with only few cases reported in medical literature. Its occurrence in multiple affected members of a family is exceptional. The aim of this presentation was to describe a Central African family with typical VDW phenotype carrying an IRF6 gene deletion. Here we reported phenotype features of members of a Central African family with VDW syndrome consisting of labioalveolar cleft, depressions of the lower lip with labial fistulae (lip pits), submucosal clefts and cleft palate. Mutation analysis by means of multiplex ligation-dependent probe amplification and chromosomal microarray revealed a 374.070 kb, deletion encompassing the entire IRF6 gene in four affected family members. Microdeletion of the entire IRF6 gene causes the classical VDW syndrome phenotype.


Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Cistos , Família , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Lábio/anormalidades , Linhagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Fenda Labial/genética , Fenda Labial/patologia , Fissura Palatina/genética , Fissura Palatina/patologia , Cistos/genética , Cistos/patologia , República Democrática do Congo , Feminino , Humanos , Lábio/patologia , Masculino
8.
Clin Nephrol ; 93(1): 34-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746731

RESUMO

BACKGROUND: To determine the role of E-selectin gene S128R polymorphism on the enlargement of renal cysts in patients with polycystic kidney disease (PKD). MATERIALS AND METHODS: 76 PKD patients with no comorbidity were enrolled in the study. Serum E-selectin levels were analyzed by enzyme-linked immunoabsorbent assay (ELISA). E-selectin gene S128R (561 A>C, rs: 5361) polymorphism was examined by polymerase chain reaction restriction fragment length (PCR-RFLP). Magnetic resonance imaging was performed at baseline evaluation and at the end of the 1st year to determine cyst enlargement and total kidney volume (TKV). RESULTS: No significant difference was identified between AA genotype and AC or CC variants of E-selectin gene S128R polymorphism in terms of age, disease duration, baseline cyst volume, cyst volume at the 12th month, baseline dominant cyst volume, and dominant cyst volume at the 12th month. In contrast, a significant difference was determined between the groups with regard to the change of TKV (2.9 ± 13.4 vs. 5.2 ± 16.3 mm3; respectively, p = 0.01). In the correlation analysis, the serum E-selectin level was significantly correlated to glucose, alanine transaminase, creatinine, calcium, phosphorus, total protein, albumin, and end diastolic volume (p = 0.0001, p = 0.001, p = 0.03, p = 0.021, p = 0.023, p = 0.002, p = 0.003, and p = 0.047, respectively). Multivariate logistic regression analysis demonstrated a 1.32-fold higher risk of cyst enlargement in patients with CC polymorphism when compared to AA genotype (p = 0.052), but not between AA and AC genotypes or CC and AC genotypes. CONCLUSION: PKD patients with CC variants of the E-selectin gene S128R polymorphism are at greater risk of cyst enlargement. The results of the present study should be confirmed with further studies with large sample size and longer duration of follow-up.


Assuntos
Cistos/patologia , Selectina E/genética , Rim/patologia , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/patologia , Adulto , Cistos/sangue , Cistos/diagnóstico por imagem , Cistos/genética , Selectina E/sangue , Feminino , Patrimônio Genético , Genótipo , Humanos , Rim/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Doenças Renais Policísticas/sangue , Doenças Renais Policísticas/diagnóstico por imagem , Polimorfismo de Fragmento de Restrição
9.
Genes (Basel) ; 10(11)2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683705

RESUMO

: The Drosophila grainyhead (grh) and vertebrate Grainyhead-like (Grhl) transcription factors are among the most critical genes for epithelial development, maintenance and homeostasis, and are remarkably well conserved from fungi to humans. Mutations affecting grh/Grhl function lead to a myriad of developmental and adult onset epithelial disease, such as aberrant skin barrier formation, facial/palatal clefting, impaired neural tube closure, age-related hearing loss, ectodermal dysplasia, and importantly, cancers of epithelial origin. Recently, mutations in the family member GRHL3 have been shown to lead to both syndromic and non-syndromic facial and palatal clefting in humans, particularly the genetic disorder Van Der Woude Syndrome (VWS), as well as spina bifida, whereas mutations in mammalian Grhl2 lead to exencephaly and facial clefting. As transcription factors, Grhl proteins bind to and activate (or repress) a substantial number of target genes that regulate and drive a cascade of transcriptional networks. A multitude of large-scale datasets have been generated to explore the grh/Grhl-dependent transcriptome, following ablation or mis-regulation of grh/Grhl-function. Here, we have performed a meta-analysis of all 41 currently published grh and Grhl RNA-SEQ, and microarray datasets, in order to identify and characterise the transcriptional networks controlled by grh/Grhl genes across disparate biological contexts. Moreover, we have also cross-referenced our results with published ChIP and ChIP-SEQ datasets, in order to determine which of the critical effector genes are likely to be direct grh/Grhl targets, based on genomic occupancy by grh/Grhl genes. Lastly, to interrogate the predictive strength of our approach, we experimentally validated the expression of the top 10 candidate grhl target genes in epithelial development, in a zebrafish model lacking grhl3, and found that orthologues of seven of these (cldn23, ppl, prom2, ocln, slc6a19, aldh1a3, and sod3) were significantly down-regulated at 48 hours post-fertilisation. Therefore, our study provides a strong predictive resource for the identification of putative grh/grhl effector target genes.


Assuntos
Sequência Conservada , Evolução Molecular , Redes Reguladoras de Genes , Proteínas Repressoras/metabolismo , Transcriptoma , Anormalidades Múltiplas/genética , Animais , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Regulação para Baixo , Drosophila , Ontologia Genética , Genômica/métodos , Humanos , Lábio/anormalidades , Proteínas Repressoras/genética , Peixe-Zebra
10.
Rev Med Liege ; 74(11): 580-585, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31729846

RESUMO

The incidental finding of renal cysts is a common clinical situation given their high prevalence (~ 50 % after the age of 50) and the continuous improvement of abdomen imaging. Diagnosis is central to appropriately dictate the management of the patient. During the diagnostic work-up, it is important to consider (i) the aspect of the cysts, (ii) their number, (iii) and their location, as well as (iv) the age of the patient and his/her personal and familial medical history, (v) the presence of extra-renal manifestations, (vi) and the renal function (including the urinary sediment). Starting from an atypical clinical case characterized by a rapidly evolving chronic kidney disease associated with bilateral renal cysts, we review the classical diagnostic work-up of kidney cysts. As a conclusion, we propose a diagnostic algorithm including both acquired and hereditary nephropathies.


Assuntos
Cistos , Nefropatias/diagnóstico , Cistos/diagnóstico , Cistos/genética , Diagnóstico Diferencial , Feminino , Testes Genéticos , Humanos , Nefropatias/genética , Masculino
11.
Am J Physiol Renal Physiol ; 317(6): F1649-F1655, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31630543

RESUMO

The severity of polycystic kidney diseases (PKD) depends on the counterbalancing of genetic predisposition and environmental factors exerting permissive or protective influence on cyst development. One poorly characterized phenomenon in the cystic epithelium is abnormal purinergic signaling. Earlier experimental studies revealed the high importance of the ionotropic P2X receptors (particularly, P2X7) in the pathophysiology of the cyst wall. To study mechanisms of P2X7 involvement in cyst growth and aspects of targeting these receptors in PKD treatment we performed a CRISPR/SpCas9-mediated global knockout of the P2rx7 gene in PCK rats, a model of autosomal recessive PKD (ARPKD). A single base insertion in exon 2 of the P2rx7 gene in the renal tissues of homozygous mutant animals leads to lack of P2X7 protein that did not affect their viability or renal excretory function. However, PCK.P2rx7 rats demonstrated slower cyst growth (but not formation of new cysts) compared with heterozygous and PCK.P2rx7+ littermates. P2X7 receptors are known to activate pannexin-1, a plasma channel capable of releasing ATP, and we found here that pannexin-1 expression in the cystic epithelium is significantly higher than in nondilated tubules. P2X7 deficiency reduces renal pannexin-1 protein expression and daily urinary ATP excretion. Patch-clamp analysis revealed that lack of P2X7 increases epithelial sodium channel activity in renal tissues and restores impaired channel activity in cysts. Interpretation of our current data in the context of earlier studies strongly suggests that P2X7 contributes to cyst growth by increasing pannexin-1-dependent pathogenic ATP release into the lumen and reduction of sodium reabsorption across the cyst walls.


Assuntos
Cistos/patologia , Nefropatias/patologia , Rim Policístico Autossômico Recessivo/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/urina , Animais , Sistemas CRISPR-Cas , Conexinas/biossíntese , Conexinas/genética , Cistos/genética , Canais Epiteliais de Sódio/metabolismo , Feminino , Técnicas de Inativação de Genes , Nefropatias/genética , Mutagênese Insercional , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Rim Policístico Autossômico Recessivo/genética , Gravidez , Ratos , Receptores Purinérgicos P2X7/genética , Sódio/metabolismo
12.
PLoS One ; 14(10): e0224501, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661532

RESUMO

Cystic echinococcosis (CE) is a worldwide zoonotic disease caused by the larval stage of Echinococcus granulosus. We investigated the presence of E. granulosus-specific DNA in the serum of CE patients by detecting the cytochrome c oxidase I (cox1) and NADH dehydrogenase subunit I (nad1) mitochondrial genes. Serum and formalin-fixed paraffin embedded (FFPE) cyst tissue samples of 80 CE patients were analyzed. The extracted DNA of samples was submitted to PCR amplification of cox1 and nad1 genes, and products were sequenced and genotyped. Nineteen (23.8%; 95% CI 15.8-34.1) serum and 78 (97.5%; 95% CI 91.3-99.3) FFPE cyst tissue samples were successfully amplified with at least one gene. Echinococcus DNA was detected in the sera of 15.0% (95% CI: 8.8-24.4) and 10.0% (95% CI: 5.2-18.5) and in cyst tissue of 91.3% (95% CI: 83.0-95.7) and 83.8% (95% CI: 74.2-90.3) of 80 patients by cox1 and nad1 gene, respectively. Four genotypes of E. granulosus were distinguished in the CE patients, with predominance of genotype G1, followed by G3, G2, and G6. The finding of E. granulosus DNA in 23.8% of serum samples from CE patients confirmed that E. granulosus releases cell-free DNA into the circulatory system, but quantities may be inadequate for the diagnosis of CE. Genotype G1 predominance suggests the sheep-dog cycle as the primary route of human infection.


Assuntos
DNA Mitocondrial/genética , Equinococose/diagnóstico , Echinococcus granulosus/genética , Adolescente , Adulto , Idoso , Animais , Sequência de Bases , Criança , Ciclo-Oxigenase 1/genética , Cistos/genética , Equinococose/sangue , Equinococose/genética , Echinococcus/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Formaldeído , Genes Mitocondriais/genética , Variação Genética/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , NADH Desidrogenase/genética , Inclusão em Parafina , Reação em Cadeia da Polimerase
14.
Nature ; 574(7777): 249-253, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578523

RESUMO

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2-5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-/- skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.


Assuntos
Diferenciação Celular , Células Epidérmicas/citologia , Epiderme/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Anormalidades Múltiplas/genética , Animais , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Células Epidérmicas/metabolismo , Epiderme/embriologia , Anormalidades do Olho/genética , Feminino , Dedos/anormalidades , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Joelho/anormalidades , Articulação do Joelho/anormalidades , Lábio/anormalidades , Metabolismo dos Lipídeos/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Sindactilia/genética , Anormalidades Urogenitais/genética
15.
EBioMedicine ; 47: 436-445, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31473186

RESUMO

BACKGROUND: Multiple preclinical studies have highlighted AMP-activated protein kinase (AMPK) as a potential therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Both metformin and canagliflozin indirectly activate AMPK by inhibiting mitochondrial function, while salsalate is a direct AMPK activator. Metformin, canagliflozin and salsalate (a prodrug dimer of salicylate) are approved for clinical use with excellent safety profile. Although metformin treatment had been shown to attenuate experimental cystic kidney disease, there are concerns that therapeutic AMPK activation in human kidney might require a higher oral metformin dose than can be achieved clinically. METHODS: In this study, we tested metformin-based combination therapies for their additive (metformin plus canagliflozin) and synergistic (metformin plus salsalate) effects and each drug individually in an adult-onset conditional Pkd1 knock-out mouse model (n = 20 male/group) using dosages expected to yield clinically relevant drug levels. FINDINGS: Compared to untreated mutant mice, treatment with salsalate or metformin plus salsalate improved kidney survival (i.e. blood urea nitrogen <20 mmol/L at the time of sacrifice) and reduced cystic kidney disease severity. However, the effects of metformin plus salsalate did not differ from salsalate alone; and neither metformin nor canagliflozin was effective. Protein expression and phosphorylation analyses indicated that salsalate treatment was associated with reduction in mTOR (mammalian target of rapamycin) activity and cellular proliferation in Pkd1 mutant mouse kidneys. Global gene expression analyses suggested that these effects were linked to restoration of mitochondrial function and suppression of inflammation and fibrosis. INTERPRETATION: Salsalate is a highly promising candidate for drug repurposing and clinical testing in ADPKD.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cistos/patologia , Doenças Renais Policísticas/patologia , Salicilatos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Biópsia , AMP Cíclico/metabolismo , Cistos/tratamento farmacológico , Cistos/genética , Cistos/metabolismo , Modelos Animais de Doenças , Monitoramento de Medicamentos , Metformina/farmacologia , Camundongos , Camundongos Knockout , Mutação , Doenças Renais Policísticas/tratamento farmacológico , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/metabolismo , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo
16.
BMJ Case Rep ; 12(9)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31488442

RESUMO

Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) spectrum are due to genetic variants in the IRF6 which phenotypically has been known to manifest with midline defects such as cleft lip and palate in VWS and additional nail, limb and genital anomalies in PPS. We report a case of VWS with the previously unrecognised phenotypic feature of hemiscrotal agenesis. While bifid scrotum has been reported in the more severe PPS, neither VWS nor PPS have previously noted hemiscrotal agenesis as part of the phenotypic picture. Hemiscrotal agenesis without evidence of any genetic anomaly has only been reported four times in the literature to date with two of these being accompanied by complete testicular descent. Treatment options include topical androgen application and/or scrotoplasty to allow for adequate testicular thermoregulation and development to occur.


Assuntos
Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Lábio/anormalidades , Escroto/anormalidades , Fenda Labial/cirurgia , Deformidades Congênitas do Pé , Mutação em Linhagem Germinativa , Humanos , Recém-Nascido , Fatores Reguladores de Interferon , Masculino , Orquidopexia , Linhagem , Escroto/cirurgia
17.
World J Pediatr ; 15(5): 454-464, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31372844

RESUMO

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis, characterized by macrocephaly, delayed motor and cognitive development, and bilateral abnormal signals in cerebral white matter (WM) with or without cysts on magnetic resonance imaging (MRI). This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance. METHODS: Clinical information and peripheral venous blood were collected from six families. Genetic analysis was performed by Sanger sequencing of GLIALCAM. GlialcamArg92Trp/+ and GlialcamLys68Met/Thr132Asn mouse models were generated based on mutations from patients (c.274C>T(p.Arg92Trp) (c.203A>T(p.Lys68Met), and c.395C>A (p.Thr132Asn))). Brain pathologies of the mouse models at different time points were analyzed. RESULTS: Six patients were clinically diagnosed with MLC. Of the six patients, five (Pt1-Pt5) presented with a heterozygous mutation in GLIALCAM (c.274C>T(p.Arg92Trp) or c.275G>C(p.Arg92Pro)) and were diagnosed with MLC2B; the remaining patient (Pt6) with two compound heterozygous mutations in GLIALCAM (c.203A>T (p.Lys68Met) and c.395C>A (p.Thr132Asn)) was diagnosed with MLC2A. The mutation c.275C>G (p.Arg92Pro) has not been reported before. Clinical manifestations of the patient with MLC2A (Pt6) progressed with regression, whereas the course of the five MLC2B patients remained stable or improved. The GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months, respectively. At 9 months, the vacuolization of the GlialcamLys68Met/ Thr132Asn mouse model was heavier than that of the GlialcamArg92Trp/+ mouse model. Decreased expression of Glialcam in GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mice may contribute to the vacuolization. CONCLUSIONS: Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation, expanding the spectrum of GLIALCAM mutations. The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated. The two mouse models with different modes of inheritance showed different degrees of brain pathological features, which were consistent with the patients' phenotype and further confirmed the pathogenicity of the corresponding mutations.


Assuntos
Proteínas de Ciclo Celular/genética , Cistos/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Animais , Grupo com Ancestrais do Continente Asiático , Moléculas de Adesão Celular Neurônio-Glia/genética , Modelos Animais de Doenças , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Mutação , Proteínas do Tecido Nervoso/genética , Prognóstico
18.
J Am Soc Nephrol ; 30(11): 2091-2102, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31395617

RESUMO

BACKGROUND: Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). METHODS: We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9, and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. RESULTS: Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. CONCLUSIONS: ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.


Assuntos
Cistos/etiologia , Heterozigoto , Hepatopatias/etiologia , Manosiltransferases/genética , Proteínas de Membrana/genética , Mutação , Rim Policístico Autossômico Dominante/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cistos/genética , Feminino , Humanos , Hepatopatias/genética , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/genética , Sequenciamento Completo do Exoma
19.
Reprod Biol Endocrinol ; 17(1): 69, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443713

RESUMO

PURPOSE: Endometriosis is one of the most common, difficult, and complicated gynecological disorders. Vascular cell adhesion molecule 1 (VCAM-1) has been reported to be aberrantly expressed in patients with endometriosis. However, the exact role and mechanism of VCAM-1 in endometriosis remains unclear. METHODS: The expression of transforming growth factor beta 1 (TGF-ß1) and VCAM-1 was determined by quantitative real-time polymerase chain reaction and western blotting. Human endometriotic cells were cultured and their responsiveness to TGF-ß1 was evaluated by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, and transwell migration and invasion assays. RESULTS: The levels of TGF-ß1 and VCAM-1 mRNA were upregulated in the endometriotic tissues. Knockdown of TGF-ß1 in endometriotic cyst stromal cells caused a marked inhibition of cell proliferation, migration, and invasion. Treatment of endometriotic cyst stromal cells with TGF-ß1 resulted in an obvious promotion of cell proliferation, migration, and invasion, and strikingly increased the protein expression of VCAM-1. Silencing of Smad3 abated TGF-ß1-stimulated VCAM-1 expression. Furthermore, the promoting effects of TGF-ß1 on the proliferation, migration, and invasion of endometriotic cyst stromal cells were blocked by silencing of VCAM-1. CONCLUSION: Knockdown of VCAM-1 impedes TGF-ß1-mediated proliferation, migration, and invasion of endometrial cells, thereby indicating that VCAM-1 may serve as a therapeutic target for endometriosis.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Cistos/genética , Endometriose/genética , Interferência de RNA , Células Estromais/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta/genética , Adulto , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Cistos/metabolismo , Cistos/patologia , Endometriose/metabolismo , Endometriose/patologia , Feminino , Humanos , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Adulto Jovem
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