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Pesquisa : G05.360.340.024.340.370 [Categoria DeCS]
Referências encontradas : 150 [refinar]
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[PMID]:29065150
[Au] Autor:Quattrocelli M; Capote J; Ohiri JC; Warner JL; Vo AH; Earley JU; Hadhazy M; Demonbreun AR; Spencer MJ; McNally EM
[Ad] Endereço:Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
[Ti] Título:Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury.
[So] Source:PLoS Genet;13(10):e1007070, 2017 Oct.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor ß (TGFß) pathway, osteopontin encoded by the SPP1 gene and latent TGFß binding protein 4 (LTBP4). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFß and TGFß-associated pathways. We identified that increased TGFß resulted in reduced expression of Anxa1 and Anxa6, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of Ltbp4 in dystrophic muscle also directly modulated sarcolemmal resealing, and Ltbp4 alleles acted in concert with Anxa6, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFß and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy.
[Mh] Termos MeSH primário: Genes Modificadores
Proteínas de Ligação a TGF-beta Latente/fisiologia
Músculo Esquelético/fisiologia
Distrofia Muscular Animal/genética
Osteopontina/metabolismo
[Mh] Termos MeSH secundário: Animais
Anexina A1/genética
Anexina A1/metabolismo
Anexina A6/genética
Anexina A6/metabolismo
Feminino
Regulação da Expressão Gênica
Masculino
Camundongos
Camundongos Endogâmicos DBA
Camundongos Knockout
Músculo Esquelético/lesões
Distrofia Muscular Animal/metabolismo
Distrofia Muscular Animal/patologia
Osteopontina/genética
Receptores de Fatores de Crescimento Transformadores beta/genética
Receptores de Fatores de Crescimento Transformadores beta/metabolismo
Recuperação de Função Fisiológica
Sarcolema/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A1); 0 (Annexin A6); 0 (LTBP-4 protein, mouse); 0 (Latent TGF-beta Binding Proteins); 0 (Receptors, Transforming Growth Factor beta); 0 (Spp1 protein, mouse); 0 (annexin A1, mouse); 106441-73-0 (Osteopontin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007070


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[PMID]:28777930
[Au] Autor:Riordan JD; Nadeau JH
[Ad] Endereço:Pacific Northwest Research Institute, Seattle, WA 98122, USA. Electronic address: jriordan@pnri.org.
[Ti] Título:From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health.
[So] Source:Am J Hum Genet;101(2):177-191, 2017 Aug 03.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called "modifier genes" that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.
[Mh] Termos MeSH primário: Epistasia Genética/genética
Redes Reguladoras de Genes/genética
Genes Modificadores/genética
Fenótipo
[Mh] Termos MeSH secundário: Alelos
Animais
Variação Genética/genética
Genótipo
Seres Humanos
Camundongos
Anotação de Sequência Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE


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[PMID]:28686619
[Au] Autor:Hammer MF; Ishii A; Johnstone L; Tchourbanov A; Lau B; Sprissler R; Hallmark B; Zhang M; Zhou J; Watkins J; Hirose S
[Ad] Endereço:ARL Division of Biotechnology, University of Arizona, Tucson, AZ, United States of America.
[Ti] Título:Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome.
[So] Source:PLoS One;12(7):e0180485, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.
[Mh] Termos MeSH primário: Epilepsias Mioclônicas/genética
Epilepsia/genética
Estudo de Associação Genômica Ampla
Canal de Sódio Disparado por Voltagem NAV1.1/genética
[Mh] Termos MeSH secundário: Alelos
Epilepsias Mioclônicas/fisiopatologia
Epilepsia/fisiopatologia
Exoma/genética
Feminino
Genes Modificadores/genética
Genótipo
Haploinsuficiência/genética
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Mutação
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180485


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[PMID]:28526948
[Au] Autor:Rodríguez-García ME; Cotrina-Vinagre FJ; Carnicero-Rodríguez P; Martínez-Azorín F
[Ad] Endereço:Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Centro de Actividades Ambulatorias (CAA), 6a Planta, Bloque E, Avda. Córdoba s/n, 28041, Madrid, Spain.
[Ti] Título:An innovative strategy to clone positive modifier genes of defects caused by mtDNA mutations: MRPS18C as suppressor gene of m.3946G>A mutation in MT-ND1 gene.
[So] Source:Hum Genet;136(7):885-896, 2017 Jul.
[Is] ISSN:1432-1203
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:We have developed a new functional complementation approach to clone modifier genes which overexpression is able to suppress the biochemical defects caused by mtDNA mutations (suppressor genes). This strategy consists in transferring human genes into respiratory chain-deficient fibroblasts, followed by a metabolic selection in a highly selective medium. We used a normalized expression cDNA library in an episomal vector (pREP4) to transfect the fibroblasts, and a medium with glutamine and devoid of any carbohydrate source to select metabolically. Growing the patient's fibroblasts in this selective medium, the deficient cells rapidly disappear unless they are rescued by the cDNA of a suppressor gene. The use of an episomal vector allows us to carry out several rounds of transfection/selection (cyclical phenotypic rescue) to enrich the rescue with true clones of suppressor genes. Using fibroblasts from a patient with epileptic encephalopathy with the m.3946G>A (p.E214K) mutation in the MT-ND1 gene, several candidate genes were identified and one of them was characterized functionally. Thus, overexpression of MRPS18C gene (that encode for bS18m protein) suppressed the molecular defects produced by this mtDNA mutation, recovering the complex I activity and reducing the ROS produced by this complex to normal levels. We suggest that modulation of bS18m expression may be an effective therapeutic strategy for the patients with this mutation.
[Mh] Termos MeSH primário: DNA Mitocondrial/genética
Genes Modificadores
Genes Supressores
Proteínas Mitocondriais/genética
Proteínas Ribossômicas/genética
[Mh] Termos MeSH secundário: Células Cultivadas
Fibroblastos/citologia
Fibroblastos/metabolismo
Regulação da Expressão Gênica
Biblioteca Gênica
Seres Humanos
Mutação
NADH Desidrogenase/genética
RNA Longo não Codificante/genética
RNA Longo não Codificante/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Análise de Sequência de DNA
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); 0 (MRPS18C protein, human); 0 (Mitochondrial Proteins); 0 (RNA, Long Noncoding); 0 (Reactive Oxygen Species); 0 (Ribosomal Proteins); EC 1.6.99.3 (NADH Dehydrogenase); EC 1.6.99.3 (NADH dehydrogenase subunit 1, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170521
[St] Status:MEDLINE
[do] DOI:10.1007/s00439-017-1812-9


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[PMID]:28476867
[Au] Autor:Chen D; Gu T; Pham TN; Zachary MJ; Hewes RS
[Ad] Endereço:Department of Biology, University of Oklahoma, Norman, Oklahoma 73019.
[Ti] Título:Regulatory Mechanisms of Metamorphic Neuronal Remodeling Revealed Through a Genome-Wide Modifier Screen in .
[So] Source:Genetics;206(3):1429-1443, 2017 Jul.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During development, neuronal remodeling shapes neuronal connections to establish fully mature and functional nervous systems. Our previous studies have shown that the RNA-binding factor ( ) is an important regulator of neuronal remodeling during metamorphosis in , and loss of leads to smaller soma size and fewer neurites in a stage-dependent manner. To shed light on the mechanisms by which regulates neuronal remodeling, we conducted a genetic modifier screen for suppressors of -dependent wing expansion defects and cellular morphological defects in a set of peptidergic neurons, the bursicon neurons, that promote posteclosion wing expansion. Out of 702 screened deficiencies that covered 86% of euchromatic genes, we isolated 24 deficiencies as candidate suppressors, and 12 of them at least partially suppressed morphological defects in mutant bursicon neurons. With RNA interference and mutant alleles of individual genes, we identified ( ) and ( ) as suppressor genes, and both of them restored the adult cellular morphology of -depleted bursicon neurons. encodes an inhibitory Smad protein that inhibits bone morphogenetic protein (BMP) signaling, raising the possibility that interacted with BMP signaling through antagonism of By manipulating expression of the BMP receptor , we found that activated BMP signaling was sufficient to rescue loss-of- phenotypes. These findings reveal mechanisms of regulation during neuronal development, and they highlight a novel genetic interaction with the BMP signaling pathway that controls morphogenesis in mature, terminally differentiated neurons during metamorphosis.
[Mh] Termos MeSH primário: Genes Modificadores
Metamorfose Biológica
Neurônios/citologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Drosophila/genética
Drosophila melanogaster/genética
Drosophila melanogaster/crescimento & desenvolvimento
Genoma de Inseto
Neurogênese
Neurônios/metabolismo
Proteínas Serina-Treonina Quinases/genética
Proteínas de Ligação a RNA/genética
Receptores de Superfície Celular/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (RNA-Binding Proteins); 0 (Receptors, Cell Surface); 0 (Shep protein, Drosophila); 0 (daughters against dpp protein, Drosophila); EC 2.7.1.- (tkv protein, Drosophila); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170507
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.117.200378


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[PMID]:28392475
[Au] Autor:Penchev V; Boueva A; Kamenarova K; Roussinov D; Tzveova R; Ivanova M; Dimitrova V; Kremensky I; Mitev V; Kaneva R; Beltcheva O
[Ad] Endereço:Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia 1463, Bulgaria.
[Ti] Título:A familial case of severe infantile nephronophthisis explained by oligogenic inheritance.
[So] Source:Eur J Med Genet;60(6):321-325, 2017 Jun.
[Is] ISSN:1878-0849
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Renal cysts are common malformation during the prenatal and postnatal period and frequent cause of chronic kidney or ESRD. More than 70 genes have been shown to play role in their pathology. Part of them are responsible for the structure and function of the cilia, which assigns a large proportion of the renal cystic diseases in the ciliopathies. Another group of genes responsible for cystic kidneys encodes transcription factors with crucial role during organogenesis. We describe here a systematic approach for identifying the genetic cause(s) of an unusually severe form of renal cystic disease in a family with multiple affected siblings. High throughput mutations screening of the parents and one of the children was applied for identifying the genetic causes of the disease. The affected child was found to have inherited 3 deleterious mutations in two nephronophthisis genes, NPHP3 and NPHP4. The possibility for epistatic interaction of the NPHP mutations as well as the modifying effect of other inherited genetic variants is discussed.
[Mh] Termos MeSH primário: Doenças Renais Císticas/genética
Cinesina/genética
Proteínas/genética
[Mh] Termos MeSH secundário: Adulto
Criança
Epistasia Genética
Feminino
Genes Modificadores
Seres Humanos
Recém-Nascido
Doenças Renais Císticas/diagnóstico
Masculino
Mutação
Linhagem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NPHP4 protein, human); 0 (Proteins); EC 3.6.1.- (nephrocystin-3, human); EC 3.6.4.4 (Kinesin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE


  7 / 150 MEDLINE  
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[PMID]:28339466
[Au] Autor:Trouvé P; Génin E; Férec C
[Ad] Endereço:Inserm, UMR1078, Brest, France.
[Ti] Título:In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.
[So] Source:PLoS One;12(3):e0173822, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.
[Mh] Termos MeSH primário: Fibrose Cística/genética
Genes Modificadores
Hepatopatias/genética
Pancreatopatias/genética
[Mh] Termos MeSH secundário: Simulação por Computador
Ciclinas/genética
Fibrose Cística/complicações
Bases de Dados Genéticas
Estudos de Associação Genética
Genótipo
Seres Humanos
Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética
Hepatopatias/complicações
Mutação
Proteínas Nucleares/genética
Pancreatopatias/complicações
Fenótipo
Fosfoproteínas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCNE2 protein, human); 0 (Cyclins); 0 (IGFBP3 protein, human); 0 (Insulin-Like Growth Factor Binding Protein 3); 0 (Nuclear Proteins); 0 (Phosphoproteins); 148998-64-5 (IFI16 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173822


  8 / 150 MEDLINE  
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[PMID]:28145423
[Au] Autor:Walker LC; Marquart L; Pearson JF; Wiggins GA; O'Mara TA; Parsons MT; Barrowdale D; McGuffog L; Dennis J; Benitez J; Slavin TP; Radice P; Frost D; Godwin AK; Meindl A; Schmutzler RK; Isaacs C; Peshkin BN; Caldes T; Hogervorst FB; Lazaro C; Jakubowska A; Montagna M; Chen X; Offit K; Hulick PJ; Andrulis IL; Lindblom A; Nussbaum RL; Nathanson KL; Chenevix-Trench G; Antoniou AC; Couch FJ; Spurdle AB; BCFR; EMBRACE; GEMO Study Collaborators; HEBON; KConFab Investigators
[Ad] Endereço:Department of Pathology, University of Otago, Christchurch, New Zealand.
[Ti] Título:Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.
[So] Source:Eur J Hum Genet;25(4):432-438, 2017 Apr.
[Is] ISSN:1476-5438
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.
[Mh] Termos MeSH primário: Proteína BRCA1/genética
Neoplasias da Mama/genética
Variações do Número de Cópias de DNA
Genes Modificadores
Neoplasias Ovarianas/genética
[Mh] Termos MeSH secundário: Adulto
Hidrocarboneto de Aril Hidroxilases/genética
Família 2 do Citocromo P450/genética
Proteínas de Ligação a DNA/genética
Feminino
Glutamato Carboxipeptidase II/genética
Heterozigoto
Seres Humanos
Glicoproteínas beta 1 Específicas da Gravidez/genética
Fatores de Transcrição TFII/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (DNA-Binding Proteins); 0 (NAALADL2 protein, human); 0 (PSG5 protein, human); 0 (Pregnancy-Specific beta 1-Glycoproteins); 0 (Transcription Factors, TFII); 0 (ZNF385A protein, human); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (CYP2A7 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 3.4.17.21 (Glutamate Carboxypeptidase II)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE
[do] DOI:10.1038/ejhg.2016.203


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[PMID]:28085748
[Au] Autor:Elalfy MS; El Sherif NH; Kamal TM; Aly NH
[Ad] Endereço:*Thalassemia Center †Molecular Genetics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
[Ti] Título:Klf10 Gene, a Secondary Modifier and a Pharmacogenomic Biomarker of Hydroxyurea Treatment Among Patients With Hemoglobinopathies.
[So] Source:J Pediatr Hematol Oncol;39(3):e155-e162, 2017 Apr.
[Is] ISSN:1536-3678
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The klf10 gene could indirectly modify γ-globin chain production and hence the level of fetal hemoglobin (HbF) ameliorating the phenotype of ß-hemoglobinopathies and the response to hydroxycarbamide (hydroxyurea [HU]) therapy. In this study, we aimed to evaluate the frequency of different genotypes for the klf10 gene in ß-thalassemia major (B-TM), ß-thalassemia intermedia (B-TI), and sickle cell disease (SCD) patients by polymerase chain reaction and to assess its relation to disease phenotypes and HU response. METHODS: This cross-sectional study included 75 patients: 50 B-TM, 12 SCD, and 13 B-TI patients (on stable HU dose). The relation of the klf10 gene polymorphism (TIEG, TIEG1, EGRα) (rs3191333: c*0.141C>T) to phenotype was studied through baseline mean corpuscular volume, HbF, and transfusion history, whereas evaluation of response to HU therapy was carried out clinically and laboratory. RESULTS: The frequency of the mutant klf10 genotype (TT) and that of the mutant allele (T) was significantly higher among B-TM patients compared with those with B-TI and SCD patients. Only homozygous SCD patients for the wild-type allele within the klf10 gene had a significantly lower transfusion frequency. The percentage of HU responders and nonresponders between different klf10 polymorphic genotypes among B-TI or SCD patients was comparable. CONCLUSIONS: Although the klf10 gene does not play a standalone role as an HbF modifier, our data support its importance in ameliorating phenotype among ß-hemoglobinopathies.
[Mh] Termos MeSH primário: Fatores de Transcrição de Resposta de Crescimento Precoce/genética
Hemoglobinopatias/tratamento farmacológico
Hidroxiureia/uso terapêutico
Fatores de Transcrição Kruppel-Like/genética
[Mh] Termos MeSH secundário: Criança
Estudos Transversais
Hemoglobina Fetal/análise
Genes Modificadores
Estudos de Associação Genética
Marcadores Genéticos/genética
Hemoglobinopatias/genética
Seres Humanos
Farmacogenética
Polimorfismo Genético
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Early Growth Response Transcription Factors); 0 (Genetic Markers); 0 (KLF10 protein, human); 0 (Kruppel-Like Transcription Factors); 9034-63-3 (Fetal Hemoglobin); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.1097/MPH.0000000000000762


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[PMID]:28076348
[Au] Autor:Mitra I; Lavillaureix A; Yeh E; Traglia M; Tsang K; Bearden CE; Rauen KA; Weiss LA
[Ad] Endereço:Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.
[Ti] Título:Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.
[So] Source:PLoS Genet;13(1):e1006516, 2017 Jan.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10-16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.
[Mh] Termos MeSH primário: Transtorno do Espectro Autista/genética
Epistasia Genética
Sistema de Sinalização das MAP Quinases/genética
Proteínas ras/genética
[Mh] Termos MeSH secundário: Linhagem Celular
Feminino
Genes Modificadores
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Células-Tronco Neurais/metabolismo
Polimorfismo de Nucleotídeo Único
Receptores Acoplados a Proteínas-G/genética
Receptores Acoplados a Proteínas-G/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170524
[Lr] Data última revisão:
170524
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006516



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