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  1 / 1869 MEDLINE  
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[PMID]:29330225
[Au] Autor:Maione L; Dwyer AA; Francou B; Guiochon-Mantel A; Binart N; Bouligand J; Young J
[Ad] Endereço:University of Paris-SudParis-Sud Medical School, Le Kremlin-Bicêtre, France.
[Ti] Título:GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing.
[So] Source:Eur J Endocrinol;178(3):R55-R80, 2018 Mar.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women. However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation. These are genetic diseases that can be transmitted to patients' offspring. Importantly, patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex; oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing and is increasingly being used in medical practice. Thus, it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission and also its role in incomplete penetrance and variable expressivity in a perspective of genetic counseling.
[Mh] Termos MeSH primário: Aconselhamento Genético
Hipogonadismo/genética
Infertilidade/genética
Síndrome de Kallmann/genética
Herança Multifatorial/genética
[Mh] Termos MeSH secundário: Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Hipogonadismo/congênito
Penetrância
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE
[do] DOI:10.1530/EJE-17-0749


  2 / 1869 MEDLINE  
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[PMID]:29220676
[Au] Autor:Abadi A; Alyass A; Robiou du Pont S; Bolker B; Singh P; Mohan V; Diaz R; Engert JC; Yusuf S; Gerstein HC; Anand SS; Meyre D
[Ad] Endereço:Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8, Canada.
[Ti] Título:Penetrance of Polygenic Obesity Susceptibility Loci across the Body Mass Index Distribution.
[So] Source:Am J Hum Genet;101(6):925-938, 2017 Dec 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)-rs1421085 (FTO; p = 8.69 × 10 ), rs6235 (PCSK1; p = 7.11 × 10 ), rs7903146 (TCF7L2; p = 9.60 × 10 ), rs11873305 (MC4R; p = 5.08 × 10 ), rs12617233 (FANCL; p = 5.30 × 10 ), rs11672660 (GIPR; p = 1.64 × 10 ), rs997295 (MAP2K5; p = 3.25 × 10 ), rs6499653 (FTO; p = 6.23 × 10 ), and rs3824755 (NT5C2; p = 7.90 × 10 )-increased significantly across the sample BMI distribution. We showed that such increases stemmed from unadjusted gene interactions that enhanced the effects of SNPs in persons with a high BMI. When 125 height-associated SNPs were analyzed for comparison, only one (<1%), rs6219 (IGF1, p = 1.80 × 10 ), showed effects that varied significantly across height percentiles. Cumulative gene scores of these SNPs (GS-BMI and GS-height) showed that only GS-BMI had effects that increased significantly across the sample distribution (BMI: p = 7.03 × 10 ; height: p = 0.499). Overall, these findings underscore the importance of gene-gene and gene-environment interactions in shaping the genetic architecture of BMI and advance a method for detecting such interactions by using only the sample outcome distribution.
[Mh] Termos MeSH primário: Estatura/genética
Índice de Massa Corporal
Herança Multifatorial/genética
Obesidade/genética
Penetrância
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Grupo com Ancestrais do Continente Europeu/genética
Frequência do Gene
Interação Gene-Ambiente
Predisposição Genética para Doença/genética
Seres Humanos
Meia-Idade
Polimorfismo de Nucleotídeo Único/genética
Locos de Características Quantitativas/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


  3 / 1869 MEDLINE  
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[PMID]:28742285
[Au] Autor:Carlston CM; Afify ZA; Palumbos JC; Bagley H; Barbagelata C; Wooderchak-Donahue WL; Mao R; Carey JC
[Ad] Endereço:Department of Pathology, University of Utah, Salt Lake City, Utah.
[Ti] Título:Variable expressivity and incomplete penetrance in a large family with non-classical Diamond-Blackfan anemia associated with ribosomal protein L11 splicing variant.
[So] Source:Am J Med Genet A;173(10):2622-2627, 2017 Oct.
[Is] ISSN:1552-4833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diamond-Blackfan anemia (DBA) is a group of clinically and genetically heterogeneous bone marrow failure disorders with or without congenital anomalies. Variable expressivity and incomplete penetrance have been observed within affected families. Diamond-Blackfan anemia-7 (DBA7), caused by heterozygous mutations in ribosomal protein L11 (RPL11), accounts for approximately 5% of DBA. DBA7 is usually characterized by early-onset bone marrow failure often accompanied by congenital malformations, especially thumb defects. Here, we present the case of a 2-year-old boy with chronic mild normocytic anemia, short stature, bilateral underdevelopment of the thumbs, atrial septal defect, and hypospadias. Hematological testing revealed slightly decreased hematocrit and hemoglobin, normal HbF, and elevated eADA. Family history included maternal relatives with thumb defects, but the mother's thumbs were normal. Clinical exome sequencing detected a maternally-inherited RPL11 variant, c.396+3A>G, that is predicted to affect splicing. A family correlation study of the identified variant demonstrates segregation with thumb anomalies in the mother's family. RNA studies suggest that the variant produces an alternative transcript that is likely susceptible to nonsense-mediated decay. This report summarizes the prevalence of non-anemia findings in DBA7 and describes a non-classical familial presentation of DBA7 more associated with thumb anomalies than with anemia.
[Mh] Termos MeSH primário: Anemia de Diamond-Blackfan/genética
Mutação
Processamento de RNA
Proteínas Ribossômicas/genética
[Mh] Termos MeSH secundário: Adulto
Pré-Escolar
Feminino
Seres Humanos
Masculino
Linhagem
Penetrância
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ribosomal Proteins); 0 (ribosomal protein L11)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1002/ajmg.a.38360


  4 / 1869 MEDLINE  
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[PMID]:29261756
[Au] Autor:Parma D; Ferrer M; Luce L; Giliberto F; Szijan I
[Ad] Endereço:Cátedra de Genética, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires. Buenos Aires. Argentina.
[Ti] Título:RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling.
[So] Source:PLoS One;12(12):e0189736, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Retinoblastoma (RB) is an inherited childhood ocular cancer caused by mutations in the tumor suppressor RB1 gene. Identification of RB1 mutations is essential to assess the risk of developing retinoblastoma in the patients´ relatives. Retinoblastoma is a potentially curable cancer and an early diagnosis is critical for survival and eye preservation. Unilateral retinoblastoma is mostly non-heritable and results from two somatic mutations whereas bilateral retinoblastoma is heritable and results from one germline and one somatic mutation, both have high penetrance, 90%. The purpose of this study was to identify causative RB1 mutations in RB patients with different clinical presentations. A comprehensive approach was used to study a cohort of 34 patients with unilateral, bilateral and trilateral retinoblastoma. Blood and tumor DNA was analyzed by sequencing and multiplex ligation-dependent probe amplification (MLPA) assay. Validation of an insertion mutation was performed by cloning the PCR product. Most of the patients in our cohort had unilateral RB, eight patients had bilateral RB and one patient had a trilateral tumor with ocular and suprasellar/sellar locations. Other tumors in addition to retinoblastoma were also found in the affected families. One patient had two syndromes, retinoblastoma and schwannomatosis, and another RB patient had a father with a retinoma. Five out of the 25 unilateral RB patients carried germinal mutations (20%), which were mostly missense mutations. The bilateral and trilateral patients carried splice-site, nonsense and frameshift mutations as well as a whole RB1 gene deletion. Missense mutations were associated with mild phenotype: unilateral retinoblastoma, retinoma or no tumor. In this study we identified causative RB1 mutations in most bilateral RB patients and in some unilateral RB patients, including five novel mutations. These data are crucial for genetic counseling and confirm the need to perform complete genetic screening for RB1 mutations in both constitutional and tumor tissues.
[Mh] Termos MeSH primário: Aconselhamento Genético
Mutação/genética
Proteína do Retinoblastoma/genética
Retinoblastoma/genética
[Mh] Termos MeSH secundário: Argentina
Pareamento de Bases
Sequência de Bases
Pré-Escolar
Éxons/genética
Feminino
Heterozigoto
Seres Humanos
Lactente
Recém-Nascido
Masculino
Linhagem
Penetrância
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Retinoblastoma Protein)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189736


  5 / 1869 MEDLINE  
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[PMID]:28835438
[Au] Autor:Dovey OM; Cooper JL; Mupo A; Grove CS; Lynn C; Conte N; Andrews RM; Pacharne S; Tzelepis K; Vijayabaskar MS; Green P; Rad R; Arends M; Wright P; Yusa K; Bradley A; Varela I; Vassiliou GS
[Ad] Endereço:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
[Ti] Título:Molecular synergy underlies the co-occurrence patterns and phenotype of -mutant acute myeloid leukemia.
[So] Source:Blood;130(17):1911-1922, 2017 Oct 26.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with internal tandem duplications (ITD) or, less commonly, or mutations. Co-occurrence of mutant with carries a significantly worse prognosis than combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound or share a number of features: gene overexpression, enhanced self-renewal, expansion of hematopoietic progenitors, and myeloid differentiation bias. However, mutants displayed significantly higher peripheral leukocyte counts, early depletion of common lymphoid progenitors, and a monocytic bias in comparison with the granulocytic bias in mutants. Underlying this was a striking molecular synergy manifested as a dramatically altered gene expression profile in , but not , progenitors compared with wild-type. Both double-mutant models developed high-penetrance AML, although latency was significantly longer with During AML evolution, both models acquired additional copies of the mutant or alleles, but only mice showed acquisition of other human AML mutations, including R132Q. We also find, using primary Cas9-expressing AMLs, that genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with c/ vs mutant AML and functionally confirm the role of genes in NPM1c-driven AML.
[Mh] Termos MeSH primário: Leucemia Mieloide Aguda/genética
Mutação/genética
Proteínas Nucleares/genética
[Mh] Termos MeSH secundário: Alelos
Animais
Diferenciação Celular
Autorrenovação Celular
Sobrevivência Celular/genética
Progressão da Doença
Dosagem de Genes
Perfilação da Expressão Gênica
Regulação Leucêmica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Células-Tronco Hematopoéticas/metabolismo
Proteínas de Homeodomínio/genética
Seres Humanos
Leucemia Mieloide Aguda/patologia
Camundongos
Células-Tronco Multipotentes/metabolismo
Mielopoese
Proteínas Nucleares/metabolismo
Penetrância
Fenótipo
Fatores de Transcrição/genética
Transcriptoma/genética
Tirosina Quinase 3 Semelhante a fms/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Homeodomain Proteins); 0 (NKX2.3 protein, human); 0 (Nuclear Proteins); 0 (Transcription Factors); 117896-08-9 (nucleophosmin); EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170825
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-01-760595


  6 / 1869 MEDLINE  
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[PMID]:28807895
[Au] Autor:Sasidharan V; Marepally S; Elliott SA; Baid S; Lakshmanan V; Nayyar N; Bansal D; Sánchez Alvarado A; Vemula PK; Palakodeti D
[Ad] Endereço:Institute for Stem Cell Biology and Regenerative Medicine, GKVK campus, Bangalore, Karnataka 560065, India.
[Ti] Título:The family of microRNAs is crucial for regeneration of the brain and visual system in the planarian .
[So] Source:Development;144(18):3211-3223, 2017 09 15.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Brain regeneration in planarians is mediated by precise spatiotemporal control of gene expression and is crucial for multiple aspects of neurogenesis. However, the mechanisms underpinning the gene regulation essential for brain regeneration are largely unknown. Here, we investigated the role of the family of microRNAs in planarian brain regeneration. The family ( ) is highly conserved in animals and regulates neurogenesis by facilitating neural differentiation, yet its role in neural wiring and brain organization is not known. We developed a novel method for delivering anti-miRs using liposomes for the functional knockdown of microRNAs. knockdown revealed a key role for these microRNAs in neuronal organization during planarian brain regeneration. Our results also demonstrated an essential role for in the generation of eye progenitors. Additionally, regulates , which encodes an axon guidance protein, either by targeting mRNA or, potentially, by modulating the canonical Notch pathway. Together, our results reveal a role for in regulating the regeneration of a functional brain and visual system.
[Mh] Termos MeSH primário: Encéfalo/fisiologia
MicroRNAs/metabolismo
Planárias/genética
Planárias/fisiologia
Regeneração
Vias Visuais/fisiologia
[Mh] Termos MeSH secundário: Animais
Fenômenos Biofísicos
Gânglios dos Invertebrados/fisiologia
Regulação da Expressão Gênica no Desenvolvimento
Técnicas de Silenciamento de Genes
Lipossomos/química
Fusão de Membrana
MicroRNAs/genética
Modelos Biológicos
Neurônios/metabolismo
Penetrância
Fenótipo
Receptores Notch/metabolismo
Reprodutibilidade dos Testes
Transdução de Sinais
Vírus/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Liposomes); 0 (MicroRNAs); 0 (Receptors, Notch)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE
[do] DOI:10.1242/dev.144758


  7 / 1869 MEDLINE  
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[PMID]:28806779
[Au] Autor:Crompton M; Purnell T; Tyrer HE; Parker A; Ball G; Hardisty-Hughes RE; Gale R; Williams D; Dean CH; Simon MM; Mallon AM; Wells S; Bhutta MF; Burton MJ; Tateossian H; Brown SDM
[Ad] Endereço:Mammalian Genetics Unit, MRC Harwell Institute, Harwell, Oxfordshire, United Kingdom.
[Ti] Título:A mutation in Nischarin causes otitis media via LIMK1 and NF-κB pathways.
[So] Source:PLoS Genet;13(8):e1006969, 2017 Aug.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-κB pathways in the development of chronic OM.
[Mh] Termos MeSH primário: Peptídeos e Proteínas de Sinalização Intracelular/genética
Quinases Lim/metabolismo
Mutação de Sentido Incorreto
NF-kappa B/metabolismo
Otite Média/genética
[Mh] Termos MeSH secundário: Alelos
Animais
Mapeamento Cromossômico
Doença Crônica
Modelos Animais de Doenças
Orelha Média/metabolismo
Etilnitrosoureia/toxicidade
Feminino
Técnicas de Genotipagem
Heterozigoto
Homozigoto
Seres Humanos
Inflamação/genética
Integrina alfa6/genética
Integrina alfa6/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Quinases Lim/genética
Masculino
Camundongos
Camundongos Knockout
NF-kappa B/genética
Neuropeptídeos/genética
Neuropeptídeos/metabolismo
Otite Média/metabolismo
Penetrância
Análise de Sequência de DNA
Regulação para Cima
Fator A de Crescimento do Endotélio Vascular/genética
Fator A de Crescimento do Endotélio Vascular/metabolismo
Quinases Ativadas por p21/genética
Quinases Ativadas por p21/metabolismo
Proteínas rac1 de Ligação ao GTP/genética
Proteínas rac1 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin alpha6); 0 (Intracellular Signaling Peptides and Proteins); 0 (NF-kappa B); 0 (Neuropeptides); 0 (Nisch protein, mouse); 0 (Rac1 protein, mouse); 0 (Vascular Endothelial Growth Factor A); 0 (vascular endothelial growth factor A, mouse); EC 2.7.11.1 (Lim Kinases); EC 2.7.11.1 (Limk1 protein, mouse); EC 2.7.11.1 (Pak1 protein, mouse); EC 2.7.11.1 (p21-Activated Kinases); EC 3.6.5.2 (rac1 GTP-Binding Protein); P8M1T4190R (Ethylnitrosourea)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006969


  8 / 1869 MEDLINE  
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[PMID]:28783164
[Au] Autor:Ivarsdottir EV; Steinthorsdottir V; Daneshpour MS; Thorleifsson G; Sulem P; Holm H; Sigurdsson S; Hreidarsson AB; Sigurdsson G; Bjarnason R; Thorsson AV; Benediktsson R; Eyjolfsson G; Sigurdardottir O; Olafsson I; Zeinali S; Azizi F; Thorsteinsdottir U; Gudbjartsson DF; Stefansson K
[Ad] Endereço:deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
[Ti] Título:Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability.
[So] Source:Nat Genet;49(9):1398-1402, 2017 Sep.
[Is] ISSN:1546-1718
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10 ), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10 and 7.3% per allele, P = 7.5 × 10 , respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r = 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.
[Mh] Termos MeSH primário: Glicemia/metabolismo
Diabetes Mellitus Tipo 2/genética
Predisposição Genética para Doença/genética
Variação Genética
[Mh] Termos MeSH secundário: Alelos
Índice de Massa Corporal
Diabetes Mellitus Tipo 2/sangue
Jejum
Feminino
Frequência do Gene
Glucoquinase/genética
Glucose-6-Fosfatase/genética
Hemoglobina A Glicada/metabolismo
Seres Humanos
Islândia
Masculino
Penetrância
Polimorfismo de Nucleotídeo Único
Fatores de Risco
Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Glycated Hemoglobin A); 0 (TCF7L2 protein, human); 0 (Transcription Factor 7-Like 2 Protein); EC 2.7.1.2 (Glucokinase); EC 3.1.3.9 (Glucose-6-Phosphatase); EC 3.1.3.9. (G6PC2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE
[do] DOI:10.1038/ng.3928


  9 / 1869 MEDLINE  
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[PMID]:28692792
[Au] Autor:Kuemmerle-Deschner JB; Verma D; Endres T; Broderick L; de Jesus AA; Hofer F; Blank N; Krause K; Rietschel C; Horneff G; Aksentijevich I; Lohse P; Goldbach-Mansky R; Hoffman HM; Benseler SM
[Ad] Endereço:University Hospital Tuebingen, Tuebingen, Germany.
[Ti] Título:Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.
[So] Source:Arthritis Rheumatol;69(11):2233-2240, 2017 Nov.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1ß (IL-1ß) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti-IL-1 treatment in patients with low-penetrance NLRP3 variants. METHODS: A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1ß release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. RESULTS: The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. CONCLUSION: Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1ß and non-IL-1ß-mediated inflammatory pathway activation.
[Mh] Termos MeSH primário: Síndromes Periódicas Associadas à Criopirina/genética
Febre/genética
Gastroenteropatias/genética
Inflamassomos/imunologia
Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Antirreumáticos/uso terapêutico
Estudos de Casos e Controles
Caspase 1/metabolismo
Morte Celular/genética
Morte Celular/imunologia
Criança
Pré-Escolar
Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico
Síndromes Periódicas Associadas à Criopirina/imunologia
Síndromes Periódicas Associadas à Criopirina/metabolismo
Oftalmopatias/tratamento farmacológico
Oftalmopatias/genética
Oftalmopatias/imunologia
Oftalmopatias/metabolismo
Feminino
Febre/tratamento farmacológico
Febre/imunologia
Febre/metabolismo
Gastroenteropatias/tratamento farmacológico
Gastroenteropatias/imunologia
Gastroenteropatias/metabolismo
Variação Genética
Perda Auditiva/tratamento farmacológico
Perda Auditiva/genética
Perda Auditiva/imunologia
Perda Auditiva/metabolismo
Seres Humanos
Lactente
Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico
Interleucina-1beta/imunologia
Nefropatias/tratamento farmacológico
Nefropatias/genética
Nefropatias/imunologia
Nefropatias/metabolismo
Masculino
Meia-Idade
NF-kappa B/metabolismo
Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia
Penetrância
Fenótipo
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Antirheumatic Agents); 0 (IL1B protein, human); 0 (Inflammasomes); 0 (Interleukin 1 Receptor Antagonist Protein); 0 (Interleukin-1beta); 0 (NF-kappa B); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (NLRP3 protein, human); EC 3.4.22.36 (Caspase 1)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE
[do] DOI:10.1002/art.40208


  10 / 1869 MEDLINE  
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Texto completo
[PMID]:28663330
[Au] Autor:Rose AM; Luo R; Radia UK; Bhattacharya SS
[Ad] Endereço:Department of Genetics, UCL Institute of Ophthalmology, London, UK.
[Ti] Título:Gene of the month: .
[So] Source:J Clin Pathol;70(9):729-732, 2017 Sep.
[Is] ISSN:1472-4146
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pre-mRNA splicing is an essential process in eukaryotic cells where the transcribed intronic sequences are removed, prior to translation into protein. PRPF31 is a ubiquitously expressed splicing factor, which aids in the assembly of the macromolecular spliceosome. Mutations in cause autosomal dominant retinitis pigmentosa (adRP), a form of retinal degeneration that causes progressive visual impairment. Interestingly, mutations in are non-penetrant, with some mutation carriers being phenotypically unaffected. In this review, the gene organisation, protein structure and biological function of PRPF31 are discussed, and the mechanisms of non-penetrance in -associated adRP are discussed.
[Mh] Termos MeSH primário: Proteínas do Olho/genética
Mutação
Retina/metabolismo
Retinite Pigmentosa/genética
Visão Ocular/genética
[Mh] Termos MeSH secundário: Proteínas do Olho/metabolismo
Marcadores Genéticos
Predisposição Genética para Doença
Hereditariedade
Seres Humanos
Penetrância
Fenótipo
Retina/fisiopatologia
Retinite Pigmentosa/metabolismo
Retinite Pigmentosa/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Eye Proteins); 0 (Genetic Markers); 0 (PRPF31 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1136/jclinpath-2016-203971



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