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An. pediatr. (2003. Ed. impr.) ; 97(4): 247-254, Oct. 2022. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-210023


Introducción: El hipogonadismo hipogonadotropo congénito (HHC) puede presentarse de manera aislada o acompañado de anosmia o de malformaciones congénitas. Más de 30 genes han sido implicados en la patogénesis de HHC; además, se han descrito varios patrones de herencia asociados a esta entidad. La creciente disponibilidad de técnicas de secuenciación masiva (NGS) ha permitido que aumente el rendimiento diagnóstico del estudio de esta patología. Pacientes y métodos: Evaluamos el rendimiento diagnóstico del estudio mediante NGS de pacientes con HHC, usando la secuenciación del exoma clínico filtrado por paneles virtuales. Además, se analizó si el diseño de estos paneles, basándose en la presencia/ausencia de microsmia/anosmia aumentaban este rendimiento diagnóstico. Resultados: Usando un panel virtual compuesto de 34 genes pudimos confirmar el diagnóstico de HHC en cinco de nueve pacientes (55%). En dos de nueve individuos (22%) estudiados se obtuvieron resultados no concluyentes. La ausencia/presencia de microsmia para la elección de genes a estudiar no mejora el rendimiento diagnóstico. Conclusiones: El abordaje del estudio genético de pacientes con HHC puede variar en función de las técnicas disponibles en cada centro, por lo que la sensibilidad del test utilizado variará, dependiendo si se utiliza secuenciación de paneles, exoma clínico o exoma completo. El análisis de todos los genes relacionados con HHC independientemente de la presencia/ausencia de microsmia pareciera el abordaje con mejor rendimiento. (AU)

Introduction: Congenital hypogonadotropic hypogonadism (CHH) can present alone or in association with anosmia or other congenital malformations. More than 30 genes have been identified as being involved in the pathogenesis of CHH with different patterns of inheritance, and the increasing availability of next generation sequencing (NGS) has increased the diagnostic yield. Methods: We analysed the diagnostic yield of NGS in patients with CHH using the clinical exome filtered with virtual panels. We also assessed whether designing panels based on the presence/absence of microsmia increased the diagnostic yield. Results: The use of a 34-gene virtual panel confirmed the diagnosis of CHH in 5 out of 9 patients (55%). In 2 out of 9 (22%), the findings were inconclusive. Applying the presence/absence of microsmia criterion to choose genes for analysis did not improve the diagnostic yield. Conclusions: The approach to the genetic study of patients with CHH varies depending on the resources of each healthcare facility, so the sensitivity of testing may vary substantially depending on whether panels, clinical exome sequencing or whole exome sequencing (WES) are used. The analysis of every genes related to CHH regardless of the presence/absence of microsmia seems to be the best approach. (AU)

Humanos , História do Século XXI , Hipogonadismo/congênito , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Epidemiologia Descritiva , Genes , Síndrome de Kallmann
Nat Commun ; 13(1): 5488, 2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123336


Single-cell gene expression data with positional information is critical to dissect mechanisms and architectures of multicellular organisms, but the potential is limited by the scalability of current data analysis strategies. Here, we present scGCO, a method based on fast optimization of hidden Markov Random Fields with graph cuts to identify spatially variable genes. Comparing to existing methods, scGCO delivers a superior performance with lower false positive rate and improved specificity, while demonstrates a more robust performance in the presence of noises. Critically, scGCO scales near linearly with inputs and demonstrates orders of magnitude better running time and memory requirement than existing methods, and could represent a valuable solution when spatial transcriptomics data grows into millions of data points and beyond.

Nature ; 609(7929): 1038-1047, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36171374


Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation1,2. Here we show that promoters are protected from oxidative damage via a process mediated by the nuclear mitotic apparatus protein NuMA (also known as NUMA1). NuMA exhibits genomic occupancy approximately 100 bp around transcription start sites. It binds the initiating form of RNA polymerase II, pause-release factors and single-strand break repair (SSBR) components such as TDP1. The binding is increased on chromatin following oxidative damage, and TDP1 enrichment at damaged chromatin is facilitated by NuMA. Depletion of NuMA increases oxidative damage at promoters. NuMA promotes transcription by limiting the polyADP-ribosylation of RNA polymerase II, increasing its availability and release from pausing at promoters. Metabolic labelling of nascent RNA identifies genes that depend on NuMA for transcription including immediate-early response genes. Complementation of NuMA-deficient cells with a mutant that mediates binding to SSBR, or a mitotic separation-of-function mutant, restores SSBR defects. These findings underscore the importance of oxidative DNA damage repair at gene regulatory elements and describe a process that fulfils this function.

Proteínas de Ciclo Celular , Dano ao DNA , Reparo do DNA , Estresse Oxidativo , Regiões Promotoras Genéticas , Proteínas de Ciclo Celular/metabolismo , Cromatina/genética , Genes , Teste de Complementação Genética , Mitose , Mutação , Estresse Oxidativo/genética , Diester Fosfórico Hidrolases/metabolismo , Poli ADP Ribosilação , Regiões Promotoras Genéticas/genética , RNA/biossíntese , RNA/genética , RNA Polimerase II/metabolismo , Fuso Acromático/metabolismo , Sítio de Iniciação de Transcrição
Science ; 377(6608): 802, 2022 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-35981035


Embryonic tissue samples reveal how pelvis shape-primed for bipedalism-comes to life.

Evolução Biológica , Genes , Pelve , Humanos , Locomoção , Pelve/anatomia & histologia , Pelve/embriologia
Nature ; 609(7928): 747-753, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36002568


Animals and fungi have radically distinct morphologies, yet both evolved within the same eukaryotic supergroup: Opisthokonta1,2. Here we reconstructed the trajectory of genetic changes that accompanied the origin of Metazoa and Fungi since the divergence of Opisthokonta with a dataset that includes four novel genomes from crucial positions in the Opisthokonta phylogeny. We show that animals arose only after the accumulation of genes functionally important for their multicellularity, a tendency that began in the pre-metazoan ancestors and later accelerated in the metazoan root. By contrast, the pre-fungal ancestors experienced net losses of most functional categories, including those gained in the path to Metazoa. On a broad-scale functional level, fungal genomes contain a higher proportion of metabolic genes and diverged less from the last common ancestor of Opisthokonta than did the gene repertoires of Metazoa. Metazoa and Fungi also show differences regarding gene gain mechanisms. Gene fusions are more prevalent in Metazoa, whereas a larger fraction of gene gains were detected as horizontal gene transfers in Fungi and protists, in agreement with the long-standing idea that transfers would be less relevant in Metazoa due to germline isolation3-5. Together, our results indicate that animals and fungi evolved under two contrasting trajectories of genetic change that predated the origin of both groups. The gradual establishment of two clearly differentiated genomic contexts thus set the stage for the emergence of Metazoa and Fungi.

Evolução Molecular , Fungos , Genoma , Genômica , Filogenia , Animais , Fungos/genética , Transferência Genética Horizontal , Genes , Genoma/genética , Genoma Fúngico/genética , Metabolismo/genética
Medicina UPB ; 41(2): 133-144, julio-diciembre 2022.
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1392154


The use of substances with addictive potential is a relevant health problem. Scientific evidence suggests that the underlying mechanisms that regulate behavioral processes in addictions involve a complex interplay between genetic and environmental factors. Therefore, this narrative review aims to provide a framework to synthesize the evidence on gene-environment-agent interactions from the perspective of the natural history of the disease and the stages of the addictive process for alcohol, nicotine, cannabis, psychostimulants, and opioids. In this review, we conducted an exhaustive literature search without time limits in PubMed, Ebsco, Lilacs, and SciELO, reviewing the title and abstract we selected original articles in humans or animals that addressed the etiology of addictions according to the methodological approach of gene-environment (G-E) interaction, including articles in Spanish, English, and Portuguese. Genetic studies have revealed the critical role of epigenetic modifiers (histone acetylation) in maintaining brain homeostasis in pathological conditions and focusing on G-E interactions will also allow characterizing subgroups (based on environmental factors) at high risk for addictive behaviors that can be targeted for specific interventions, Thus, treatment strategies should encompass a combination of psychosocial interventions with gene therapy involving pharmacological manipulations of histones that may contribute to design better therapies and perhaps lead to more successful management of drug dependencies.

El consumo de sustancias con potencial adictivo es un problema relevante de salud. La evidencia científica sugiere que los mecanismos subyacentes que regulan los procesos comportamentales en las adicciones involucran un complejo interjuego entre factores genéticos y ambientales. Por lo tanto, esta revisión narrativa tiene como objetivo aportar un marco de referencia que permita sintetizar la evidencia sobre interacciones genes- ambiente-agente desde la perspectiva de la historia natural de la enfermedad y los estadios del proceso adictivo para: alcohol, nicotina, cannabis, psicoestimulantes y opioides. En esta revisión realizamos una búsqueda exhaustiva de la literatura sin límites de tiempo en PubMed, Ebsco, Lilacs y SciELO, revisando el título y el resumen se seleccionaron artículos originales en humanos o animales que abordaran la etiología de las adiciones según el enfoque metodológico de interacción entre genes y ambiente (G-A), incluyendo artículos en español, inglés y portugués. Los estudios genéticos han revelado el papel crítico de los modificadores epigenéticos (acetilación de las histonas) en mantener la homeóstasis cerebral en condiciones patológicas y enfocarse en las interacciones G-A también permitirá caracterizar subgrupos (basados en los factoresambientales) de alto riesgo para conductas adictivas que pueden ser objeto de intervenciones específicas, por lo que, las estrategias de tratamiento deben englobar una combinación de intervenciones psicosociales con terapia génica que involucren las manipulaciones farmacológicas de las histonas que pueden contribuir a diseñar mejores terapias y tal vez conducir a un manejo más exitoso de las drogodependencias.

O consumo de substâncias com potencial viciante é um relevante problema de saúde. Evidências científicas sugerem que os mecanismos subjacentes que regulam os processos comportamentais em vícios envolvem uma interação complexa entre fatores genéticos e ambientais. Portanto, esta revisão narrativa visa fornecer um quadro de referência que permita sintetizar as evidências sobre interações gene-ambiente-agente sob a perspectiva da história natural da doença e as etapas do processo de dependência para: álcool, nicotina, cannabis, psicoestimulantes e opióides. Nesta revisão, realizamos uma busca exaustiva da literatura sem limites de tempo no PubMed, Ebsco , Lilacs e SciELO, revisando o título e o resumo, foram selecionados artigos originais em humanos ou animais que abordassem a etiologia dos acréscimos de acordo com a abordagem metodológica de interação entre genes e ambiente (GA), incluindo artigos em espanhol, inglês e português. Estudos genéticos revelaram o papel crítico dos modificadores epigenéticos (acetilação de histonas) na manutenção da homeostase cerebral em condições patológicas, e o direcionamento das interações GA também permitirá caracterizar subgrupos (com base em fatores ambientais) de alto risco para comportamentos aditivos que podem ser alvo de ataques específicos. intervenções, portanto, as estratégias de tratamento devem abranger uma combinação de intervenções psicossociais com terapia gênica envolvendo manipulações farmacológicas de histonas que podem contribuir para projetar melhores terapias e talvez levar a um manejo mais bem-sucedido das dependências de drogas.

Humanos , Animais , Comportamento Aditivo , Cannabis , Epigenômica , Genes , Analgésicos Opioides
Arq. ciências saúde UNIPAR ; 26(2): 159-174, maio-ago. 2022.
Artigo em Português | LILACS | ID: biblio-1372969


A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.

Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.

Humanos , Masculino , Feminino , Peso Corporal/genética , Genes/genética , Obesidade/genética , Exercício Físico , Índice de Massa Corporal , Expressão Gênica/genética , Leptina/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 4 de Melanocortina/genética , Dieta/métodos , Melanocortinas/genética , Receptores para Leptina/genética , Epigenômica , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Hipotálamo
Arch. bronconeumol. (Ed. impr.) ; 58(4): 311-322, abr. 2022. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-206199


Introduction: Tobacco consumption and radon exposure are considered the first and second most common causes of lung cancer, respectively. The aim of this study was to analyze both whether selected genetic polymorphisms in loci that are in DNA repair pathways, are related to non-small-cell lung cancer (NSCLC) and whether they may modulate the association between residential radon exposure and lung cancer in both smokers and never smokers.Methods: A multicentre, hospital-based, case–control study with 826 cases and 1201 controls was designed in a radon-prone area. Genotyping was determined in whole blood and residential radon exposure was measured in participants’ dwellings.Results: Attending to tobacco exposure, the variant in the gene NBN (rs1805794) was associated with lung cancer in never smokers (OR 2.72; 95%1.44–5.2) and heavy smokers (OR 3.04; 95%CI 1.21–7.69). The polymorphism with the highest lung cancer association was OGG1 (rs125701), showing an OR of 8.04 (95%CI 1.64–58.29) for its homozygous variant genotype in heavy smokers. Attending to indoor radon exposure (>200Bq/m3), rs1452584, for its homozygous variant genotype, showed the highest association (OR 3.04 (95%CI 1.15–8.48).Conclusion: The genes analyzed seem to have no association with the fully adjusted model, but they might modulate lung cancer association when different categories of tobacco consumption are considered (i.e. heavy smokers). This association may similarly be elevated for those individuals having high indoor radon exposures, though at a minor extent. (AU)

Introducción: El consumo de tabaco y la exposición al radón se consideran la primera y la segunda causa más frecuentes de cáncer de pulmón, respectivamente. El objetivo de este estudio fue analizar si determinados polimorfismos genéticos en los loci que forman parte de la cascada de reparación del ADN se asocian con el cáncer de pulmón de célula no pequeña, y también si es posible que modifiquen la asociación entre la exposición al radón en el hogar y el cáncer de pulmón tanto en fumadores como en no fumadores.Métodos: Se diseñó un estudio multicéntrico hospitalario de casos y controles con 826 casos y 1.201 controles en un área proclive a la presencia de radón. Se determinó el genotipo en sangre y se midió la exposición al radón en el lugar de residencia de los participantes.Resultados: Analizando la exposición al tabaco, la variante del gen NBN (rs1805794) se asoció con el cáncer de pulmón en no fumadores (OR 2,72; IC 95% 1,44-5,2) y grandes fumadores (OR 3,04; IC 95% 1,21-7,69). El polimorfismo con mayor asociación con el cáncer de pulmón fue OGG1 (rs125701), con una OR de 8,04 (IC 95% 1,64-58,29) para la variante genotípica en homocigosis en grandes fumadores. En cuanto a la exposición al radón en interiores (>200Bq/m3), rs1452584 en homocigosis mostró la asociación más fuerte (OR 3,04; IC 95% 1,15-8,48).Conclusión: Los genes que se analizaron no muestran asociación con el modelo completamente ajustado, pero podrían modificar la asociación con el cáncer de pulmón cuando se consideran diferentes categorías de consumo de tabaco (esto es, grandes fumadores). Esta asociación podría aumentar de forma similar en aquellos individuos que están expuestos al radón en interiores, aunque en menor medida. (AU)

Humanos , Poluição por Fumaça de Tabaco , Radônio , Neoplasias Pulmonares , não Fumantes , Genes
Rev. psiquiatr. salud ment. (Barc., Ed. impr.) ; 15(2): 88-93, abr.-jun. 2022. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-206811


Introduction: Alterations in the genes of lysine methylation as Lysine-specific demethylase 6B (KDM6B) have been associated with multiple neurodevelopmental disorders. Until now, there are few cases in the literature attributed to KDM6B mutations. This gap may be due to the fact that the exome sequencing technique is still being implemented in routine clinical practice.Material and methods: A case is presented with its clinical and phenotypic characteristics. The sequence exome analysis was done with the Nimblegen SeqCap EZ MedExome capture kit+mtDNA 47Mb. The psychopathological approach from mental health was carried out through individual and family interviews, the Conner's questionnaires, ADHD rating scale, as well as the psychometry.Results: A frameshift variant in the KDM6B gene related to neurodevelopmental disorders with facial and body dysmorphia was obtained. The case was oriented as a neurodevelopmental disorder secondary to a genetic alteration and a comorbid Attention Deficit Hyperactivity Disorder (ADHD).Conclusions: The clinical peculiarities shared by patients identified with the KDM6B mutation, raises the need to recognize it as a particular entity. The possibility of applying the exome sequencing technique to patients with syndromic phenotype and developmental impairment may clarify its etiopathogenesis. It is highly probable that the complexity of these cases requires an approach by a multidisciplinary team that includes genetics, neurology and psychiatry, among other specialties. The coordinated approach is essential to have a comprehensive vision of the case. (AU)

Introducción: Las alteraciones en los genes de metilación de lisina como la desmetilasa 6B de lisina (KDM6B) se han asociado con múltiples trastornos del neurodesarrollo. Hasta ahora, existen pocos casos en la literatura atribuidos a mutaciones del gen KDM6B. Esta brecha puede deberse al hecho de que la técnica de secuenciación del exoma aún está en fase de implementación en la práctica clínica habitual.Material y métodos: Se presenta un caso con características clínicas y fenotípicas. El análisis de secuenciación exómica se realizó con el kit de captura Nimblegen SeqCap EZ MedExome + mtDNA 47Mb. La aproximación psicopatológica desde salud mental se realizó a través de entrevistas individuales, familiares, los cuestionarios Conners, ADHD rating scale, así como la psicometría.Resultados: Se obtuvo una variante de cambio en el gen KDM6B que ha sido relacionado con trastornos del neurodesarrollo con dismorfias faciales y corporales. El caso fue orientado como un trastorno del neurodesarrollo secundario a una alteración genética, un trastorno por déficit de atención e hiperactividad (TDAH).Conclusiones: Las peculiaridades clínicas que comparten los pacientes identificados con la mutación KDM6B, plantea la necesidad de reconocerla como una entidad particular. La posibilidad de aplicar la técnica de secuenciación del exoma a pacientes con fenotipo sindrómico y retraso generalizado en el desarrollo puede aclarar su etiopatogenia. Es muy probable que la complejidad de estos casos requiera el abordaje de un equipo multidisciplinar que incluya genetistas, neurólogos y psiquiatras, entre otras especialidades. El enfoque coordinado es fundamental para obtener una visión integral del caso. (AU)

Humanos , Genes , Transtornos do Neurodesenvolvimento , Transtorno do Deficit de Atenção com Hiperatividade
Genes (Basel) ; 13(1)2022 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-35052457


Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1-5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions ("actionable genes"). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in "actionable genes", including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.

Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Genes , Mutação , Medicina de Precisão , Testes Genéticos , Humanos
Acta sci., Health sci ; 44: e56960, Jan. 14, 2022.
Artigo em Inglês | LILACS | ID: biblio-1367539


Colorectal cancer is the 4thcause of cancer death; with considering the growth process of this cancer and the necessity of early diagnosis, the purpose of the research is to state the LncRNA 00970, LncRNA UCAI,and the Wntgene before and after the treatment by 5-Azacytidine epigenetic medicine, to reach the biomarker in the very first steps of colorectal cancer. In this experiment, the human colon cancer cell line (HT29) treated with different concentrations of 5-aza-2'-deoxycytidine (5-aza-dC) was utilized to induce DNA demethylation; Quantitative PCR (qPCR) was used to measure LncRNA UCA1and LncRNA LINC00970 and Wntexpression. There was a significant relationship between the expression of LncRNA 00970, LncRNA UCAI,and the Wntgene and its effects on colorectal (p < 0.05). The Wntgene was treated by 1 and 10 of 5-Azacytidine epigenetic medicine, which then experienced decreases. In LncRNA UCAI and LncRNA00970 in dose 1 micromolar of 5-Azacytidine had decrement and increment of expressionrespectively that explains their efficiency but in treatment by dose 10 mM of this medicine, no significant LncRNA expression difference was detected, 5-azacitidine has a direct impact on its target genes and LncRNAs.Therefore, it can be used in the early diagnosis of colorectal cancer.

Técnicas In Vitro/métodos , DNA/análise , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/terapia , Neoplasias do Colo/diagnóstico , Diagnóstico Precoce , Azacitidina/análise , Azacitidina/antagonistas & inibidores , Biomarcadores , Neoplasias Colorretais/mortalidade , Linhagem Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/terapia , Epigenômica , RNA Longo não Codificante , RNA Longo não Codificante/efeitos dos fármacos , Genes
Reprod Sci ; 29(2): 475-479, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34231177


Kallmann syndrome (KS) is a rare genetic disorder that is characterized by idiopathic hypogonadotropic hypogonadism associated with anosmia. Genetic variants in ANOS1 gene are the most common mutations associated with X-linked recessive form of KS. Canonical ± 1 or 2 splice site variants in ANOS1 have been described to be responsible for KS. Here, we identified a novel noncanonical splice site variant (c.1062+4T>C) in ANOS1 gene in two siblings with KS by whole-exome sequencing (WES). Sanger sequencing showed this mutation was inherited from their mother, whose brother was a KS patient as well. Through the functional assay in vitro, we found that this mutation resulted in a 50-bp deletion of exon 7, which caused frameshift mutation leading to a premature termination of translation and a truncated anosmin-1 protein. Our results revealed that this noncanonical splice site variant is involved in KS. Thus, it is suggested that we should pay attention to the noncanonical splice site variants when using molecular genetic diagnostics of KS.

Proteínas da Matriz Extracelular/genética , Genes/genética , Síndrome de Kallmann/genética , Proteínas do Tecido Nervoso/genética , Isoformas de Proteínas/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Irmãos , Sequenciamento Completo do Exoma , Adulto Jovem
Reprod Sci ; 29(2): 480-496, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34697776


Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy of indistinguishable etiopathogenesis that is liable to entail genetic and environmental machinery synergistically interacting with its phenotypic expression. It has been hypothesized that the environment secondarily interacts with genes to define the quantifiable phenotype in a primary, genetically determined, hyper-androgenic ovarian defect. The severity and prevalence of the disease are escalating due to uncontrolled diet and lifestyle, the influence of multiple environmental factors as well as genetic disorders. Many candidate genes have been identified to be one of the causes of PCOS. Different studies have been carried out to find the genetic correlation of PCOS. The mutational landscape analysis scans the entire genes for SNPs which usually occurs more frequently in patients and not in healthy individuals. In this study, an extensive computational analysis of all reported nsSNPs of the 27 selected PCOS-related genes was performed to infer the most pathogenic forms associated with PCOS. As a result, 28 genetic variants from 11 genes were predicted to be most harmful. Results of the present study can be useful for building an integrative genotype-phenotype database for further studies.

Predisposição Genética para Doença/genética , Síndrome do Ovário Policístico/genética , Simulação por Computador , Feminino , Genes/genética , Testes Genéticos , Humanos , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética
PLoS Comput Biol ; 17(12): e1009669, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34871311


There is a growing realization that multi-way chromatin contacts formed in chromosome structures are fundamental units of gene regulation. However, due to the paucity and complexity of such contacts, it is challenging to detect and identify them using experiments. Based on an assumption that chromosome structures can be mapped onto a network of Gaussian polymer, here we derive analytic expressions for n-body contact probabilities (n > 2) among chromatin loci based on pairwise genomic contact frequencies available in Hi-C, and show that multi-way contact probability maps can in principle be extracted from Hi-C. The three-body (triplet) contact probabilities, calculated from our theory, are in good correlation with those from measurements including Tri-C, MC-4C and SPRITE. Maps of multi-way chromatin contacts calculated from our analytic expressions can not only complement experimental measurements, but also can offer better understanding of the related issues, such as cell-line dependent assemblies of multiple genes and enhancers to chromatin hubs, competition between long-range and short-range multi-way contacts, and condensates of multiple CTCF anchors.

Cromatina , Mapeamento Cromossômico/métodos , Regulação da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , DNA/química , DNA/metabolismo , Elementos Facilitadores Genéticos/genética , Genes/genética , Genômica , Humanos
Genome Biol ; 22(1): 338, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34906207


Aggregating transcriptomics data across hospitals can increase sensitivity and robustness of differential expression analyses, yielding deeper clinical insights. As data exchange is often restricted by privacy legislation, meta-analyses are frequently employed to pool local results. However, the accuracy might drop if class labels are inhomogeneously distributed among cohorts. Flimma ( ) addresses this issue by implementing the state-of-the-art workflow limma voom in a federated manner, i.e., patient data never leaves its source site. Flimma results are identical to those generated by limma voom on aggregated datasets even in imbalanced scenarios where meta-analysis approaches fail.

Expressão Gênica , Privacidade , Pesquisa Biomédica , Redes de Comunicação de Computadores , Segurança Computacional/legislação & jurisprudência , Segurança Computacional/normas , Bases de Dados Factuais/legislação & jurisprudência , Bases de Dados Factuais/normas , Expressão Gênica/ética , Genes , Regulamentação Governamental , Humanos , Aprendizado de Máquina
Med Sci Monit ; 27: e933425, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34928926


BACKGROUND The aim of this study was to identify feature autophagy-related genes (ARGs) in systemic lupus erythematosus (SLE), evaluate their diagnostic value, and further explore DNA methylation and expression levels in the pathogenesis of SLE. MATERIAL AND METHODS WGCNA was used to construct network and selected hub genes based on gene expression dataset GSE81622. ARGS were overlapped with hub genes, and feature ARGs were identified. A diagnostic model was established by these feature ARGs using LASSO. GSE96879 was used to analyze the methylation levels of feature ARGs. The expression and methylation levels of feature ARGs were verified using RT-PCR and methylation-specific PCR. RESULTS We found that 55 hub genes were highly connected to the red module of WGCNA, and ARGs were extracted from the Human Autophagy Database and the GO_AUTOPHAGY gene set. Overlapping of 55 hub gene with ARGs resulted in 18 feature ARGs. S100A8, MyD88, and NCR3 from the 18 feature ARGs showed higher good diagnostic value for SLE. Five differentially methylated positions locating to S100A8, MyD88, and NCR3 genes were identified from GSE96879. After validation tests, RT-PCR showed that gene expressions of MyD88 and S100A8 were increased in the PBMCs samples of SLE patients compared with healthy controls, whereas NCR3 was the opposite. MSP found that cg24898863 (S100A8) was hypomethylated, while cg27490128 (NCR3) was hypermethylated in the SLE group, and S100A8 and NCR3 methylation were positively correlated with their expressions. CONCLUSIONS Our present study identified the potential roles of feature ARGs in SLE diagnosis, and shows correlation among DNA methylation and gene expressions of these feature ARGs in SLE.

Autofagia/genética , Metilação de DNA/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Feminino , Genes/genética , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Fatores de Risco
Rev. Ciênc. Méd. Biol. (Impr.) ; 20(3): 480-484, dez 20, 2021. fig
Artigo em Português | LILACS | ID: biblio-1354354


Introdução: o gene TERT codifica a subunidade catalítica da telomerase responsável pelo alongamento dos telômeros no final dos cromossomos. Mutações na região promotora do gene TERT resultam em superexpressão da subunidade catalítica e promovem aumento da atividade da telomerase, fatos que levam ao aumento da incidência do câncer. No carcinoma anaplásico da tireoide, essas mutações são preditores de pior prognóstico e estão associadas a comportamento clínico agressivo, incluindo alta frequência de recidivas, metástases a distância e morte específica pela doença. Objetivo: relatar o caso de uma paciente idosa portadora de carcinoma anaplásico da tireoide, cujo teste de sequenciamento genético revelou a mutação do promotor TERT C228T. Caso clínico: mulher idosa, 66 anos, diagnosticada inicialmente com nódulo tireoidiano, o qual cresceu rapidamente em um curto período de tempo. Diante da suspeita de neoplasia maligna, a paciente foi submetida a tireoidectomia total, com realização de esvaziamento cervical. Os estudos anatomopatológico e imuno-histoquímico do tumor confirmaram o carcinoma. Estudos moleculares realizados a partir da tecnologia do sequenciamento de nova geração negaram a presença de fusões gênicas, porém detectaram a mutação TERT C228T. Discussão: a identificação da mutação no promotor TERT C288T reforça a hipótese de que mutações TERT são frequentes em tumores tireoidianos mais agressivos, como é o caso do carcinoma anaplásico da tireoide. Conclusão: os dados apresentados neste estudo reforçam a premissa de que mutações no promotor TERT são preditores de pior prognóstico e de comportamento clínico mais agressivo.

Introduction: the TERT gene encodes the catalytic telomerase subunit responsible for elongating telomeres at the end of chromosomes. Mutations in the promoter region of the TERT gene result in overexpression of the catalytic subunit and promote increased telomerase activity, facts that lead to an increased incidence of cancer. In anaplastic thyroid carcinoma, these mutations are predictors of worse prognosis and are associated with aggressive clinical behavior, including a high frequency of relapses, distant metastases, and diseasespecific death. Objective: to report the case of an elderly patient with anaplastic thyroid carcinoma, whose gene sequencing test revealed a TERT C228T promoter mutation. Case report: Elderly woman, 66 years old, initially diagnosed with a thyroid nodule, which grew rapidly in a short period of time. Given the suspicion of malignant neoplasm, the patient underwent total thyroidectomy, with neck dissection. The anatomopathological and immunohistochemical studies of the tumor confirmed the carcinoma. Molecular studies performed using next-generation sequencing technology denied the presence of gene fusions, but detected the TERT C228T mutation. Discussion: identification of the mutation in the TERT C288T promoter reinforces the hypothesis that TERT mutations are frequent in more aggressive thyroid tumors, such as anaplastic thyroid carcinoma. Conclusion: data presented in this study reinforce the premise that mutations in the TERT promoter are predictors of worse prognosis and more aggressive clinical behavior.

Humanos , Feminino , Idoso , Tireoidectomia , Telomerase , Carcinoma Anaplásico da Tireoide , Mutação , Genes
Rev. Ciênc. Méd. Biol. (Impr.) ; 20(3): 375-386, dez 20, 2021. tab, fig
Artigo em Português | LILACS | ID: biblio-1354189


Introdução: o sistema RANKL (receptor-ativador do fator nuclear-ligante κB)/RANK (receptor ativador do NF-kB)/OPG (osteoprotegrina) Introdução: o sistema OPG (osteoprotegrina)/RANK (receptor ativador do NF-kB)/RANKL (receptor-ativador do fator nuclear-ligante κB) regula os processos fisiológicos e patológicos da remodelação óssea. Polimorfismos genéticos nos genes OPG, RANK e RANKL têm sido associados a doenças, em diferentes populações. Objetivo: Descrever a frequência e o potencial regulatório dos polimorfismos do sistema OPG, RANK e RANKL em uma população brasileira; avaliar o seu potencial como marcadores genéticos informativos de ancestralidade; comparar com patologias associadas em outras populações. Metodologia: neste estudo, 506 indivíduos adultos, participantes de uma coorte acometidos de asma e periodontite, tiveram o DNA genômico extraído e genotipado, utilizando-se a plataforma Illumina. As plataformas NCBI, RegulomeDB, Haploview 4.2 e rSNPBase foram consultadas e utilizadas para análises. Resultados e Discussão: os polimorfismos mais frequentes na população estudada foram o rs3102724 no gene OPG, com frequência de menor alelo (MAF) de 46%; o rs4941129 em RANK, MAF 50%; e o rs9525641 em RANKL, MAF 46%. Os rs3134063 (1f) em OPG, rs17069898 (1f) em RANK e rs2200287 (1d) em RANKL apresentaram maior impacto funcional. Em OPG e RANK, nove polimorfismos se caracterizaram como marcadores genéticos informativos de ancestralidade, com predomínio nas populações YRI (africanos) e CEU (europeus). Os nove polimorfismos, com função intrônica, apresentaram MAF entre 2 a 46% na população-alvo e foram associados a patologias do metabolismo ósseo em outras populações. Conclusão: polimorfismos dos genes estudados se mostraram frequentes na população estudada e tiveram seus alelos mais frequentes associados a doenças em populações ancestrais. Sugere-se que sejam realizados mais estudos.

Introduction: The OPG (osteoprotegerin)/ RANK (NF-kB activating receptor)/ RANKL (nuclear-binding factor κB receptor-activating system regulates the physiological and pathological processes of bone remodeling. Genetic polymorphisms (SNPs) in OPG, RANK and RANKL genes have been associated with diseases in different populations. Objective: Describe the regulatory frequency and potential of SNPs in OPG, RANK and RANKL in a Brazilian population; assess their potential as informative genetic markers of ancestry; compare with pathologies associated with these polymorphisms in other populations. Methods: in this study, 506 adult individuals, participating in a cohort involving asthma and periodontitis, had genomic DNA extracted and genotyped using the Illumina platform. The NCBI, RegulomeDB, Haploview 4.2 and rSNPBase platforms were consulted and used for analysis. Results and discussion: the most frequent polymorphisms in the studied population were the rs3102724 in the OPG gene, with the lowest allele frequency (MAF) of 46%; rs4941129 in RANK, MAF 50% and rs9525641 in RANKL, MAF 46%. The rs3134063 (1f) in OPG, rs17069898 (1f) in RANK and rs2200287 (1d) in RANKL, had greater functional impact. In OPG and RANK, 9 SNPs were characterized as informative genetic markers of ancestry, predominantly in YRI (African) and CEU (European) populations. These 9 SNPs, with intronic function, presented MAF between 2 and 46% in our population, and were associated with pathologies in bone metabolism in other populations. Conclusion: SNPs of the studied genes were found to be frequent in the studied population and had their most frequent alleles associated with diseases in ancestral populations. It is suggested that further studies be carried out

Humanos , Masculino , Feminino , Adulto , Polimorfismo Genético , Ligante RANK , Genes , Periodontite , Asma , Simulação por Computador
Rev. ecuat. pediatr ; 22(3): 1-7, 30 de diciembre del 2021.
Artigo em Espanhol | LILACS | ID: biblio-1352458


Introducción: El síndrome de Noonan es un trastorno genético de herencia autosómica dominante con una expresión fenotípica variable. Se encuentra dentro de las enfermedades conocidas como rasopatías, producidas por las mutaciones en los genes RAS. Los pacientes se caracterizan por dismorfismo facial, talla baja, enfermedad cardíaca congénita, alteraciones músculos esqueléticas y en algunos casos discapacidad intelectual. Caso clínico: En el presente reporte se describe el caso de un paciente masculino de un mes de edad que acude a consulta externa, presentando dismorfismo facial y estenosis pulmonar, por lo que se realiza un seguimiento multidisciplinario por sospecha de Síndrome de Noonan. A partir del cuarto mes desarrolló linfedema en la zona del deltoides. Evolución: A los 7 meses de vida se realiza secuenciación de exoma, encontrando una variante patogénica en el gen SOS1, confirmando el diagnóstico de dicho síndrome. Conclusión: Este caso documenta la presencia de síndrome de Noonan con mutación del gen SOS1 con dismorfología facial típica, estenosis de la válvula pulmonar, criptorquidia y displasia linfática con linfedema del deltoides, hallazgo no descrito en casos previos.

Introduction: Noonan syndrome is a dominant autosomal inherited ge-netic disorder with variable phenotypic expression. It is found within diseases known as rasopathies and is pro-duced by mutations in RAS genes. Patients are character-ized by facial dysmorphism, short stature, congenital heart disease, musculoskeletal disorders, and, in some cases, intellectual disability. Clinical case: This report describes the case of a one-month-old male patient who comes to the outpatient clinic, presenting with facial dysmorphism and pulmonary steno-sis, for which a multidisciplinary follow-up is carried out due to suspicion of Noonan syndrome. From the fourth month, the patient developed lymphedema in the deltoid area. Evolution: At 7 months of age, exome sequencing was per-formed, finding a pathogenic vari-ant in the SOS1 gene and confirming the diagnosis of this syndrome. Conclusion: This case documents the presence of Noonan syndrome with a mutation of the SOS1 gene with typical facial dysmorphology, pulmonary valve stenosis, cryptor-chidism and lymphatic dysplasia with deltoid.

Humanos , Pré-Escolar , Anormalidades Craniofaciais , Cardiopatias Congênitas , Síndrome de Noonan , Anormalidades Congênitas , Genes