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[PMID]:28969385
[Au] Autor:Alcantara D; Timms AE; Gripp K; Baker L; Park K; Collins S; Cheng C; Stewart F; Mehta SG; Saggar A; Sztriha L; Zombor M; Caluseriu O; Mesterman R; Van Allen MI; Jacquinet A; Ygberg S; Bernstein JA; Wenger AM; Guturu H; Bejerano G; Gomez-Ospina N; Lehman A; Alfei E; Pantaleoni C; Conti V; Guerrini R; Moog U; Graham JM; Hevner R; Dobyns WB; O'Driscoll M; Mirzaa GM
[Ad] Endereço:Genome Damage and Stability Centre, University of Sussex, Sussex, UK.
[Ti] Título:Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly.
[So] Source:Brain;140(10):2610-2622, 2017 Oct 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.
[Mh] Termos MeSH primário: Deficiências do Desenvolvimento/genética
Megalencefalia/genética
Mutação/genética
Proteínas Proto-Oncogênicas c-akt/genética
[Mh] Termos MeSH secundário: Encéfalo/diagnóstico por imagem
Criança
Deficiências do Desenvolvimento/diagnóstico por imagem
Deficiências do Desenvolvimento/patologia
Feminino
Estudos de Associação Genética
Células HEK293
Seres Humanos
Imunoprecipitação
Imagem por Ressonância Magnética
Masculino
Megalencefalia/diagnóstico por imagem
Megalencefalia/patologia
Mutagênese Sítio-Dirigida/métodos
Fosfatidilinositóis/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphatidylinositols); EC 2.7.11.1 (AKT3 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx203


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[PMID]:28822558
[Au] Autor:Peterman CM; Vadeboncoeur S; Mulliken JB; Fishman SJ; Liang MG
[Ad] Endereço:Tufts University School of Medicine, Boston, Massachusetts; Department of Dermatology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Vascular Anomalies Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
[Ti] Título:Wilms tumor screening in diffuse capillary malformation with overgrowth and macrocephaly-capillary malformation: A retrospective study.
[So] Source:J Am Acad Dermatol;77(5):874-878, 2017 Nov.
[Is] ISSN:1097-6787
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies) syndrome is associated with regional bony and/or soft tissue overgrowth, capillary malformation, and an increased risk for Wilms tumor. OBJECTIVE: To evaluate the frequency of Wilms tumor in patients with 2 similar conditions: diffuse capillary malformation with overgrowth (DCMO) and macrocephaly-capillary malformation (M-CM). METHODS: Culling our Vascular Anomalies Center database, we retrospectively reviewed patients in whom DCMO and M-CM had been diagnosed and who were evaluated between 1998 and 2016 for possible development of Wilms tumor. Patients younger than 8 years of age at their last visit and not seen in more than 2 years were contacted for follow-up. RESULTS: The study comprised 89 patients: 67 with DCMO, 17 with M-CM, and 5 with an indeterminate diagnosis. No case of Wilms tumor was found in these groups. LIMITATIONS: Some patients were younger than 8 years of age at last follow-up visit and the sample size was small. CONCLUSION: Patients with DCMO do not appear to be at increased risk for Wilms tumor. Screening is probably unnecessary in DCMO unless there is associated hemihypertrophy. Although there were no cases in our cohort, there are 2 reports of M-CM associated with Wilms tumor in the literature.
[Mh] Termos MeSH primário: Anormalidades Múltiplas/epidemiologia
Capilares/anormalidades
Neoplasias Renais/epidemiologia
Megalencefalia/epidemiologia
Dermatopatias Vasculares/epidemiologia
Telangiectasia/congênito
Malformações Vasculares/epidemiologia
Tumor de Wilms/epidemiologia
[Mh] Termos MeSH secundário: Anormalidades Múltiplas/diagnóstico por imagem
Anormalidades Múltiplas/patologia
Distribuição por Idade
Capilares/diagnóstico por imagem
Capilares/patologia
Pré-Escolar
Estudos de Coortes
Comorbidade
Bases de Dados Factuais
Feminino
Seguimentos
Seres Humanos
Incidência
Lactente
Recém-Nascido
Neoplasias Renais/diagnóstico por imagem
Neoplasias Renais/patologia
Lipoma/diagnóstico por imagem
Lipoma/epidemiologia
Lipoma/patologia
Imagem por Ressonância Magnética
Masculino
Megalencefalia/diagnóstico por imagem
Megalencefalia/patologia
Anormalidades Musculoesqueléticas/diagnóstico por imagem
Anormalidades Musculoesqueléticas/epidemiologia
Anormalidades Musculoesqueléticas/patologia
Triagem Neonatal
Nevo/diagnóstico por imagem
Nevo/epidemiologia
Nevo/patologia
Doenças Raras
Estudos Retrospectivos
Medição de Risco
Índice de Gravidade de Doença
Distribuição por Sexo
Dermatopatias Vasculares/diagnóstico por imagem
Dermatopatias Vasculares/patologia
Telangiectasia/diagnóstico por imagem
Telangiectasia/epidemiologia
Telangiectasia/patologia
Fatores de Tempo
Malformações Vasculares/diagnóstico por imagem
Malformações Vasculares/patologia
Tumor de Wilms/diagnóstico por imagem
Tumor de Wilms/patologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170821
[St] Status:MEDLINE


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[PMID]:28658095
[Au] Autor:Pavone P; Praticò AD; Rizzo R; Corsello G; Ruggieri M; Parano E; Falsaperla R
[Ad] Endereço:aUniversity-Hospital "Policlinico-Vittorio Emanuele" bDepartment of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry cMaurice Wohl Clinical Neuroscience Institute, King's College London, London, UK dDepartment of Maternal and Child Health, University of Palermo, Palermo eNational Research Council, Section of Catania, Catania, Italy.
[Ti] Título:A clinical review on megalencephaly: A large brain as a possible sign of cerebral impairment.
[So] Source:Medicine (Baltimore);96(26):e6814, 2017 Jun.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Megalencephaly and macrocephaly present with a head circumference measurement 2 standard deviations above the age-related mean. However, even if pathologic events resulting in both megalencephaly and macrocephaly may coexist, a distinction between these two entities is appropriate, as they represent clinical expression of different disorders with a different approach in clinical work-up, overall prognosis, and treatment. Megalencephaly defines an increased growth of cerebral structures related to dysfunctional anomalies during the various steps of brain development in the neuronal proliferation and/or migration phases or as a consequence of postnatal abnormal events. The disorders associated with megalencephaly are classically defined into 3 groups: idiopathic or benign, metabolic, and anatomic. In this article, we seek to underline the clinical aspect of megalencephaly, emphasizing the main disorders that manifest with this anomaly in an attempt to properly categorize these disorders within the megalencephaly group.
[Mh] Termos MeSH primário: Megalencefalia
[Mh] Termos MeSH secundário: Seres Humanos
Megalencefalia/classificação
Megalencefalia/diagnóstico
Megalencefalia/metabolismo
Megalencefalia/psicologia
Estudos Observacionais como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000006814


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[PMID]:28605459
[Au] Autor:Pettersson M; Viljakainen H; Loid P; Mustila T; Pekkinen M; Armenio M; Andersson-Assarsson JC; Mäkitie O; Lindstrand A
[Ad] Endereço:Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 77, Sweden.
[Ti] Título:Copy Number Variants Are Enriched in Individuals With Early-Onset Obesity and Highlight Novel Pathogenic Pathways.
[So] Source:J Clin Endocrinol Metab;102(8):3029-3039, 2017 Aug 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity. Objective: To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue. Design and Setting: A case-control study in a tertiary academic center. Participants: CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses. Main Outcome Measures: We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue. Results: We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5). Conclusions: Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.
[Mh] Termos MeSH primário: Obesidade Pediátrica/genética
RNA Mensageiro/metabolismo
Gordura Subcutânea/metabolismo
[Mh] Termos MeSH secundário: Anormalidades Múltiplas/genética
Fosfatase Ácida/genética
Adolescente
Adulto
Proteínas Mutadas de Ataxia Telangiectasia/genética
Transtorno Autístico/genética
Autoantígenos/genética
Estudos de Casos e Controles
Proteínas de Ciclo Celular/genética
Criança
Pré-Escolar
Deleção Cromossômica
Transtornos Cromossômicos/genética
Duplicação Cromossômica/genética
Cromossomos Humanos Par 1/genética
Cromossomos Humanos Par 16/genética
Cromossomos Humanos Par 22/genética
Hibridização Genômica Comparativa
Variações do Número de Cópias de DNA
Enzimas Reparadoras do DNA/genética
Proteínas de Ligação a DNA/genética
Síndrome de DiGeorge/genética
Proteínas da Matriz Extracelular/genética
Feminino
Seres Humanos
Hidrolases/genética
Deficiência Intelectual/genética
Fatores de Transcrição Kruppel-Like/genética
Masculino
Megalencefalia/genética
Proteínas dos Microfilamentos/genética
Proteínas Nucleares/genética
Proteínas/genética
Irmãos
Fatores de Transcrição/genética
Transcriptoma
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantigens); 0 (BAZ2B protein, human); 0 (Cell Cycle Proteins); 0 (DNA-Binding Proteins); 0 (EFEMP1 protein, human); 0 (Extracellular Matrix Proteins); 0 (KLF15 protein, human); 0 (Kruppel-Like Transcription Factors); 0 (MACROD2 protein, human); 0 (MAMLD1 protein, human); 0 (MBD5 protein, human); 0 (Microfilament Proteins); 0 (Nuclear Proteins); 0 (PCM1 protein, human); 0 (Proteins); 0 (RNA, Messenger); 0 (SORBS1 protein, human); 0 (Transcription Factors); EC 2.7.11.1 (ATR protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 3.- (Hydrolases); EC 3.1.3.2 (Acid Phosphatase); EC 3.1.3.2 (acid phosphatase-like protein 1, human); EC 6.5.1.- (DNA Repair Enzymes)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2017-00565


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[PMID]:28566443
[Au] Autor:Leiter SM; Parker VER; Welters A; Knox R; Rocha N; Clark G; Payne F; Lotta L; Harris J; Guerrero-Fernández J; González-Casado I; García-Miñaur S; Gordo G; Wareham N; Martínez-Glez V; Allison M; O'Rahilly S; Barroso I; Meissner T; Davies S; Hussain K; Temple K; Barreda-Bonis AC; Kummer S; Semple RK
[Ad] Endereço:Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
[Ti] Título:Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase.
[So] Source:Eur J Endocrinol;177(2):175-186, 2017 Aug.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Genetic activation of the insulin signal-transducing kinase causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction. METHODS: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed. RESULTS: In the first three patients, mosaic mutations in (p.Gly118Asp or p.Glu726Lys) or (p.Gly373Arg) were found. In different tissue samples available from one patient, the p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in had neither clinical nor biochemical evidence of hypoglycaemia. CONCLUSIONS: Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy.
[Mh] Termos MeSH primário: Classe I de Fosfatidilinositol 3-Quinases/genética
Hipoglicemia/genética
Insulina/genética
Megalencefalia/genética
Mosaicismo
Fosfatidilinositol 3-Quinases/genética
Proteínas Proto-Oncogênicas c-akt/genética
[Mh] Termos MeSH secundário: Pré-Escolar
Feminino
Seres Humanos
Hipoglicemia/diagnóstico
Hipoglicemia/metabolismo
Insulina/metabolismo
Masculino
Megalencefalia/diagnóstico
Megalencefalia/metabolismo
Fosfatidilinositol 3-Quinases/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.- (phosphoinositol-3 kinase regulatory subunit 2, human); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.11.1 (AKT2 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.1530/EJE-17-0132


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[PMID]:28402856
[Au] Autor:Platt RJ; Zhou Y; Slaymaker IM; Shetty AS; Weisbach NR; Kim JA; Sharma J; Desai M; Sood S; Kempton HR; Crabtree GR; Feng G; Zhang F
[Ad] Endereço:Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biosystems S
[Ti] Título:Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits.
[So] Source:Cell Rep;19(2):335-350, 2017 Apr 11.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8 mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8 animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.
[Mh] Termos MeSH primário: Transtorno do Espectro Autista/genética
Proteínas de Ligação a DNA/genética
Megalencefalia/genética
[Mh] Termos MeSH secundário: Animais
Transtorno do Espectro Autista/patologia
Cromatina/genética
Corpo Estriado/patologia
Modelos Animais de Doenças
Regulação da Expressão Gênica no Desenvolvimento
Mutação em Linhagem Germinativa
Histonas/genética
Seres Humanos
Megalencefalia/patologia
Camundongos
Via de Sinalização Wnt/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (DNA-Binding Proteins); 0 (Histones); 0 (duplin protein, mouse)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE


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[PMID]:28190287
[Au] Autor:Takagi M; Dobashi K; Nagahara K; Kato M; Nishimura G; Fukuzawa R; Narumi S; Hasegawa T
[Ad] Endereço:Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
[Ti] Título:A novel de novo germline mutation Glu40Lys in AKT3 causes megalencephaly with growth hormone deficiency.
[So] Source:Am J Med Genet A;173(4):1071-1076, 2017 Apr.
[Is] ISSN:1552-4833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Germline or somatic gain-of-function mutations in the v-akt murine thymoma viral oncogene homolog 3 (AKT3) have been reported to cause syndromic megalencephaly. We describe a novel germline mutation, p.Glu40Lys, in AKT3. Phenotypically, the patient presented with megalencephaly with hypotonia, apparent connective tissue laxity, and growth hormone (GH) deficiency. To our knowledge, this is the first instance of a patient with megalencephaly with GH deficiency, harboring a germline de novo mutation in AKT3. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Mutação em Linhagem Germinativa
Hormônio do Crescimento/deficiência
Megalencefalia/genética
Hipotonia Muscular/genética
Proteínas Proto-Oncogênicas c-akt/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Grupo com Ancestrais do Continente Asiático
Sequência de Bases
Pré-Escolar
Tecido Conjuntivo/metabolismo
Tecido Conjuntivo/patologia
Exoma
Expressão Gênica
Hormônio do Crescimento/genética
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Megalencefalia/diagnóstico
Megalencefalia/etnologia
Megalencefalia/patologia
Hipotonia Muscular/diagnóstico
Hipotonia Muscular/etnologia
Hipotonia Muscular/patologia
Fenótipo
Proteínas Proto-Oncogênicas c-akt/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
9002-72-6 (Growth Hormone); EC 2.7.11.1 (AKT3 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170213
[St] Status:MEDLINE
[do] DOI:10.1002/ajmg.a.38099


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[PMID]:28126652
[Au] Autor:Hertecant J; Komara M; Nagi A; Al-Zaabi O; Fathallah W; Cui H; Yang Y; Eng CM; Al Sorkhy M; Ghattas MA; Al-Gazali L; Ali BR
[Ad] Endereço:Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates; Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
[Ti] Título:A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins.
[So] Source:Eur J Med Genet;60(4):212-216, 2017 Apr.
[Is] ISSN:1878-0849
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Pathogenic variants in theP21 protein (Cdc42/Rac)-activated kinase 3gene (PAK3) lead to a rare non syndromic X-linked intellectual disability. The protein encoded by this gene forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1 proteins which then mediates a variety of cellular processes. So far, mutations in PAK3 gene have been reported in few families affected with intellectual disability associated with neurological manifestations such as speech defect, behavioral problem, brain structural abnormalities, microcephaly and cerebral palsy. In this study whole exome sequencing revealed a de novo likely pathogenic variant in PAK3 gene in monozygotic twins presented with intellectual disability, speech delay, behavioral problems and macrocephaly. Macrocephaly was noticed in our patients from birth at 35 weeks of gestation. This aspect of the phenotype has not been previously reported in other documented cases with pathogenic mutations in PAK3 gene. Our findings extend the phenotype of this disorder to include macrocephaly and offers further clues to the importance of the serine/threonine-protein kinase 3 (PAK3) protein in brain development and function.
[Mh] Termos MeSH primário: Ligação Genética
Deficiência Intelectual/genética
Megalencefalia/genética
Mutação
Quinases Ativadas por p21/genética
[Mh] Termos MeSH secundário: Domínio Catalítico
Ciclo Celular
Proliferação Celular
Pré-Escolar
Cristalografia por Raios X
Doenças em Gêmeos
Exoma
Saúde da Família
Pai
Feminino
Seres Humanos
Masculino
Mães
Linhagem
Fenótipo
Gêmeos Monozigóticos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.1 (PAK3 protein, human); EC 2.7.11.1 (p21-Activated Kinases)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170320
[Lr] Data última revisão:
170320
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE


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[PMID]:28118382
[Au] Autor:Reis VN; Kitajima JP; Tahira AC; Feio-Dos-Santos AC; Fock RA; Lisboa BC; Simões SN; Krepischi AC; Rosenberg C; Lourenço NC; Passos-Bueno MR; Brentani H
[Ad] Endereço:LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil.
[Ti] Título:Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder.
[So] Source:PLoS One;12(1):e0170386, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations-single nucleotide variants (SNVs) or small insertions and deletions (indels)-with probable functional impacts. With aCGH, we identified, in both siblings, a duplication in the 4p16.3 region and a deletion at 8p23.3, inherited by a paternal balanced translocation, t(4, 8) (p16; p23). Exome variant analysis found a total of 316 variants, of which 102 were shared by both siblings, 128 were in the male sibling exome data, and 86 were in the female exome data. Our integrative network analysis showed that the siblings' shared translocation could explain their similar syndromic phenotype, including overgrowth, macrocephaly, and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, which are important to the robustness of the network and contribute to the understanding of the broader spectrum of psychiatric symptoms. This study shows the importance of using an integrative approach to explore genotype-phenotype variability.
[Mh] Termos MeSH primário: Transtorno do Espectro Autista/genética
Cromossomos Humanos Par 4/genética
Cromossomos Humanos Par 8/genética
Hibridização Genômica Comparativa
Variações do Número de Cópias de DNA
Exoma/genética
Estudos de Associação Genética
Translocação Genética
[Mh] Termos MeSH secundário: Criança
Cromossomos Humanos Par 4/ultraestrutura
Cromossomos Humanos Par 8/ultraestrutura
Feminino
Duplicação Gênica
Redes Reguladoras de Genes
Seres Humanos
Hibridização in Situ Fluorescente
Deficiência Intelectual/genética
Transtornos de Aprendizagem/genética
Masculino
Megalencefalia/genética
Proteínas do Tecido Nervoso/genética
Técnicas de Amplificação de Ácido Nucleico
Deleção de Sequência
Irmãos
Síndrome
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nerve Tissue Proteins)
[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:170125
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0170386


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[PMID]:28086757
[Au] Autor:Negishi Y; Miya F; Hattori A; Johmura Y; Nakagawa M; Ando N; Hori I; Togawa T; Aoyama K; Ohashi K; Fukumura S; Mizuno S; Umemura A; Kishimoto Y; Okamoto N; Kato M; Tsunoda T; Yamasaki M; Kanemura Y; Kosaki K; Nakanishi M; Saitoh S
[Ad] Endereço:Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan.
[Ti] Título:A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly.
[So] Source:BMC Med Genet;18(1):4, 2017 Jan 13.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Constitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder. METHODS: Thirteen patients with an increased head circumference and neurological symptoms participated in the study. To evaluate the activation of the mTOR pathway, we performed western blot analysis to determine the expression levels of phosphorylated S6 ribosomal protein (phospho-S6 protein) in lymphoblastoid cell lines from 12 patients. Multiplex targeted sequencing analysis for 15 genes involved in the mTOR pathway was performed on 12 patients, and whole-exome sequencing was performed on one additional patient. Clinical features and MRI findings were also investigated. RESULTS: We identified pathogenic mutations in six (AKT3, 1 patient; PIK3R2, 2 patients; PTEN, 3 patients) of the 13 patients. Increased expression of phospho-S6 protein was demonstrated in all five mutation-positive patients in whom western blotting was performed, as well as in three mutation-negative patients. Developmental delay, dysmorphic facial features were observed in almost all patients. Syndactyly/polydactyly and capillary malformations were not observed, even in patients with AKT3 or PIK3R2 mutations. There were no common phenotypes or MRI findings among these patients. CONCLUSIONS: A combination of genetic and biochemical methods successfully identified mTOR pathway involvement in nine of 13 (approximately 70%) patients with megalencephaly, indicating a major contribution of the pathway to the pathogenesis of megalencephaly. Our combined approach could be useful to identify patients who are suitable for future clinical trials using an mTOR inhibitor.
[Mh] Termos MeSH primário: Megalencefalia/diagnóstico
PTEN Fosfo-Hidrolase/genética
Fosfatidilinositol 3-Quinases/genética
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Quinases S6 Ribossômicas/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Linhagem Celular
Criança
Pré-Escolar
Feminino
Seres Humanos
Masculino
Megalencefalia/genética
Megalencefalia/metabolismo
Mutação
PTEN Fosfo-Hidrolase/metabolismo
Fosforilação
Proteínas Proto-Oncogênicas c-akt/metabolismo
Análise de Sequência de DNA/métodos
Transdução de Sinais
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.- (phosphoinositol-3 kinase regulatory subunit 2, human); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (AKT3 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (Ribosomal Protein S6 Kinases); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (PTEN protein, human)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170518
[Lr] Data última revisão:
170518
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170115
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-016-0363-6



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