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  1 / 4156 MEDLINE  
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[PMID]:29181930
[Au] Autor:Skråning S; Lindskog BV
[Ti] Título:The Zika outbreak in Brazil: An unequal burden..
[So] Source:Tidsskr Nor Laegeforen;137(22), 2017 11 28.
[Is] ISSN:0807-7096
[Cp] País de publicação:Norway
[La] Idioma:nor
[Mh] Termos MeSH primário: Efeitos Psicossociais da Doença
Microcefalia
Infecção pelo Zika virus
[Mh] Termos MeSH secundário: Brasil/epidemiologia
Assistência à Saúde/organização & administração
Surtos de Doenças/economia
Feminino
Saúde Global
Acesso aos Serviços de Saúde
Seres Humanos
Recém-Nascido
Microcefalia/economia
Microcefalia/virologia
Mães/psicologia
Saúde Única
Pobreza
Gravidez
Complicações Infecciosas na Gravidez/economia
Complicações Infecciosas na Gravidez/epidemiologia
Complicações Infecciosas na Gravidez/virologia
Previdência Social
Saúde da Mulher
Zika virus/isolamento & purificação
Infecção pelo Zika virus/congênito
Infecção pelo Zika virus/economia
Infecção pelo Zika virus/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.4045/tidsskr.17.0655


  2 / 4156 MEDLINE  
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[PMID]:29346415
[Au] Autor:Jobst-Schwan T; Schmidt JM; Schneider R; Hoogstraten CA; Ullmann JFP; Schapiro D; Majmundar AJ; Kolb A; Eddy K; Shril S; Braun DA; Poduri A; Hildebrandt F
[Ad] Endereço:Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
[Ti] Título:Acute multi-sgRNA knockdown of KEOPS complex genes reproduces the microcephaly phenotype of the stable knockout zebrafish model.
[So] Source:PLoS One;13(1):e0191503, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Until recently, morpholino oligonucleotides have been widely employed in zebrafish as an acute and efficient loss-of-function assay. However, off-target effects and reproducibility issues when compared to stable knockout lines have compromised their further use. Here we employed an acute CRISPR/Cas approach using multiple single guide RNAs targeting simultaneously different positions in two exemplar genes (osgep or tprkb) to increase the likelihood of generating mutations on both alleles in the injected F0 generation and to achieve a similar effect as morpholinos but with the reproducibility of stable lines. This multi single guide RNA approach resulted in median likelihoods for at least one mutation on each allele of >99% and sgRNA specific insertion/deletion profiles as revealed by deep-sequencing. Immunoblot showed a significant reduction for Osgep and Tprkb proteins. For both genes, the acute multi-sgRNA knockout recapitulated the microcephaly phenotype and reduction in survival that we observed previously in stable knockout lines, though milder in the acute multi-sgRNA knockout. Finally, we quantify the degree of mutagenesis by deep sequencing, and provide a mathematical model to quantitate the chance for a biallelic loss-of-function mutation. Our findings can be generalized to acute and stable CRISPR/Cas targeting for any zebrafish gene of interest.
[Mh] Termos MeSH primário: Técnicas de Silenciamento de Genes
Microcefalia/genética
Modelos Biológicos
RNA/genética
Peixe-Zebra/genética
[Mh] Termos MeSH secundário: Animais
Sistemas CRISPR-Cas
Sequenciamento de Nucleotídeos em Larga Escala
Mutação INDEL
Mutagênese
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
63231-63-0 (RNA)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191503


  3 / 4156 MEDLINE  
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[PMID]:29240727
[Au] Autor:Satterfield-Nash A; Kotzky K; Allen J; Bertolli J; Moore CA; Pereira IO; Pessoa A; Melo F; Santelli ACFES; Boyle CA; Peacock G
[Ti] Título:Health and Development at Age 19-24 Months of 19 Children Who Were Born with Microcephaly and Laboratory Evidence of Congenital Zika Virus Infection During the 2015 Zika Virus Outbreak - Brazil, 2017.
[So] Source:MMWR Morb Mortal Wkly Rep;66(49):1347-1351, 2017 Dec 15.
[Is] ISSN:1545-861X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In November 2015, the Brazilian Ministry of Health (MOH) declared the Zika virus outbreak a public health emergency after an increase in microcephaly cases was reported in the northeast region of the country (1). During 2015-2016, 15 states in Brazil with laboratory-confirmed Zika virus transmission reported an increase in birth prevalence of microcephaly (2.8 cases per 10,000 live births), significantly exceeding prevalence in four states without confirmed transmission (0.6 per 10,000) (2). Although children with microcephaly and laboratory evidence of Zika virus infection have been described in early infancy (3), their subsequent health and development have not been well characterized, constraining planning for the care and support of these children and their families. The Brazilian MOH, the State Health Secretariat of Paraíba, and CDC collaborated on a follow-up investigation of the health and development of children in northeastern Brazil who were reported to national surveillance with microcephaly at birth. Nineteen children with microcephaly at birth and laboratory evidence of Zika virus infection were assessed through clinical evaluations, caregiver interviews, and review of medical records. At follow-up (ages 19-24 months), most of these children had severe motor impairment, seizure disorders, hearing and vision abnormalities, and sleep difficulties. Children with microcephaly and laboratory evidence of Zika virus infection have severe functional limitations and will require specialized care from clinicians and caregivers as they age.
[Mh] Termos MeSH primário: Deficiências do Desenvolvimento/epidemiologia
Surtos de Doenças
Microcefalia/virologia
Infecção pelo Zika virus/congênito
Zika virus/isolamento & purificação
[Mh] Termos MeSH secundário: Brasil/epidemiologia
Estudos de Casos e Controles
Pré-Escolar
Técnicas de Laboratório Clínico
Feminino
Seguimentos
Seres Humanos
Lactente
Recém-Nascido
Masculino
Microcefalia/epidemiologia
Gravidez
Complicações Infecciosas na Gravidez
Infecção pelo Zika virus/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180119
[Lr] Data última revisão:
180119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE
[do] DOI:10.15585/mmwr.mm6649a2


  4 / 4156 MEDLINE  
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[PMID]:29191162
[Au] Autor:Tan L; Bi B; Zhao P; Cai X; Wan C; Shao J; He X
[Ad] Endereço:Clinical Research Center, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430016, China.
[Ti] Título:Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review.
[So] Source:BMC Med Genet;18(1):141, 2017 12 01.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Microcephaly is a disorder characterized by severe impairment in brain development, reduced brain and head size. Congenital severe microcephaly is very rare, and NDE1 deletion and genetic mutations are important contributors. CASE PRESENTATION: Single nucleotide polymorphism (SNP) chromosomal microarray analysis (CMA) and muation screening of NDE1 gene were performed in an 8-month patient with severe congenital microcephaly, and/or his parents. Genetic studies found a 16p13.11 deletion containing NDE1 gene, and a novel NDE1 mutation c.555_556GC > CT on the non-deleted homolog, inherited from his phenotypically normal parents, respectively. The 2 bp nucleotide change results in a missense mutation p.K185 N and a nonsense mutation p.Q186X. We also conducted literaturte review to compare the clinical phenotypes of our patient to those of cases previously reported with NDE1 mutations, and found all patients had mental retardation, severe microcephaly, and corpus callosum agenesis. CONCLUSION: This is the first Chinese reported with microcephaly caused by NDE1 mutations. NDE1 is a critical pathogenetic gene in severe congenital microcephaly. Sequencing NDE1 and CMA in patients with severe congenital microcephaly may be warranted.
[Mh] Termos MeSH primário: Deleção Cromossômica
Microcefalia/diagnóstico
Microcefalia/genética
Proteínas Associadas aos Microtúbulos/genética
[Mh] Termos MeSH secundário: Encéfalo/fisiopatologia
Cromossomos Humanos Par 16/genética
Códon sem Sentido
Seres Humanos
Lactente
Deficiência Intelectual/genética
Masculino
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Codon, Nonsense); 0 (Microtubule-Associated Proteins); 0 (Nde1 protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171231
[Lr] Data última revisão:
171231
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0501-9


  5 / 4156 MEDLINE  
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[PMID]:28464862
[Au] Autor:Duerinckx S; Verhelst H; Perazzolo C; David P; Desmyter L; Pirson I; Abramowicz M
[Ad] Endereço:IRIBHM, Université Libre de Bruxelles, Brussels, Belgium. saduerin@ulb.ac.be.
[Ti] Título:Severe congenital microcephaly with AP4M1 mutation, a case report.
[So] Source:BMC Med Genet;18(1):48, 2017 05 02.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset. CASE PRESENTATION: We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly. CONCLUSIONS: Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly.
[Mh] Termos MeSH primário: Complexo 4 de Proteínas Adaptadoras/genética
Microcefalia/genética
Mutação
[Mh] Termos MeSH secundário: Seres Humanos
Recém-Nascido
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Protein Complex 4)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171231
[Lr] Data última revisão:
171231
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0412-9


  6 / 4156 MEDLINE  
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[PMID]:27775637
[Au] Autor:Wang JN; Ling F
[Ad] Endereço:Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Hangzhou 310051, China. jnwang@cdc.zj.cn.
[Ti] Título:Zika Virus Infection and Microcephaly: Evidence for a Causal Link.
[So] Source:Int J Environ Res Public Health;13(10), 2016 10 20.
[Is] ISSN:1660-4601
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Zika virus (ZIKV) is a flavivirus related to the Dengue, yellow fever and West Nile viruses. Since the explosive outbreaks of ZIKV in Latin America in 2015, a sudden increase in the number of microcephaly cases has been observed in infants of women who were pregnant when they contracted the virus. The severity of this condition raises grave concerns, and extensive studies on the possible link between ZIKV infection and microcephaly have been conducted. There is substantial evidence suggesting that there is a causal link between ZIKV and microcephaly, however, future studies are warranted to solidify this association. To summarize the most recent evidence on this issue and provide perspectives for future studies, we reviewed the literature to identify existing evidence of the causal link between ZIKV infection and microcephaly within research related to the epidemics, laboratory diagnosis, and possible mechanisms.
[Mh] Termos MeSH primário: Feto/virologia
Microcefalia/etiologia
Microcefalia/virologia
Infecção pelo Zika virus/complicações
Infecção pelo Zika virus/fisiopatologia
Zika virus/patogenicidade
[Mh] Termos MeSH secundário: Surtos de Doenças
Feminino
Seres Humanos
Lactente
América Latina/epidemiologia
Microcefalia/epidemiologia
Microcefalia/fisiopatologia
Gravidez
Infecção pelo Zika virus/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171218
[Lr] Data última revisão:
171218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  7 / 4156 MEDLINE  
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[PMID]:29053855
[Au] Autor:Niturad CE; Lev D; Kalscheuer VM; Charzewska A; Schubert J; Lerman-Sagie T; Kroes HY; Oegema R; Traverso M; Specchio N; Lassota M; Chelly J; Bennett-Back O; Carmi N; Koffler-Brill T; Iacomino M; Trivisano M; Capovilla G; Striano P; Nawara M; Rzonca S; Fischer U; Bienek M; Jensen C; Hu H; Thiele H; Altmüller J; Krause R; May P; Becker F; Balling R; Biskup S; Haas SA; Nürnberg P; van Gassen KLI; Lerche H; Zara F; Maljevic S; Leshinsky-Silver E; EuroEPINOMICS Consortium
[Ad] Endereço:Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
[Ti] Título:Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features.
[So] Source:Brain;140(11):2879-2894, 2017 Nov 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.
[Mh] Termos MeSH primário: Encefalopatias/genética
Fissura Palatina/genética
Deficiências do Desenvolvimento/genética
Epilepsia/genética
Facies
Deficiência Intelectual/genética
Nistagmo Patológico/genética
Receptores de GABA-A/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Animais
Criança
Pré-Escolar
Feminino
Variação Genética
Seres Humanos
Masculino
Microcefalia/genética
Mutagênese Sítio-Dirigida
Oócitos/metabolismo
Técnicas de Patch-Clamp
Linhagem
Receptores de GABA-A/metabolismo
Síndrome
Xenopus laevis
Adulto Jovem
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABRA3 protein, human); 0 (Receptors, GABA-A); 56-12-2 (gamma-Aminobutyric Acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx236


  8 / 4156 MEDLINE  
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[PMID]:29030384
[Au] Autor:Petribu NCL; Aragao MFV; van der Linden V; Parizel P; Jungmann P; Araújo L; Abath M; Fernandes A; Brainer-Lima A; Holanda A; Mello R; Sarteschi C; Duarte MDCMB
[Ad] Endereço:Barão de Lucena Hospital, Recife, Brazil natachacalheiros@yahoo.com.br.
[Ti] Título:Follow-up brain imaging of 37 children with congenital Zika syndrome: case series study.
[So] Source:BMJ;359:j4188, 2017 Oct 13.
[Is] ISSN:1756-1833
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: To compare initial brain computed tomography (CT) scans with follow-up CT scans at one year in children with congenital Zika syndrome, focusing on cerebral calcifications. Case series study. Barão de Lucena Hospital, Pernambuco state, Brazil. 37 children with probable or confirmed congenital Zika syndrome during the microcephaly outbreak in 2015 who underwent brain CT shortly after birth and at one year follow-up. Differences in cerebral calcification patterns between initial and follow-up scans. 37 children were evaluated. All presented cerebral calcifications on the initial scan, predominantly at cortical-white matter junction. At follow-up the calcifications had diminished in number, size, or density, or a combination in 34 of the children (92%, 95% confidence interval 79% to 97%), were no longer visible in one child, and remained unchanged in two children. No child showed an increase in calcifications. The calcifications at the cortical-white matter junction which were no longer visible at follow-up occurred predominately in the parietal and occipital lobes. These imaging changes were not associated with any clear clinical improvements. The detection of cerebral calcifications should not be considered a major criterion for late diagnosis of congenital Zika syndrome, nor should the absence of calcifications be used to exclude the diagnosis.
[Mh] Termos MeSH primário: Encéfalo/diagnóstico por imagem
Calcinose/diagnóstico por imagem
Tomografia Computadorizada por Raios X/métodos
Infecção pelo Zika virus/diagnóstico
Zika virus/isolamento & purificação
[Mh] Termos MeSH secundário: Encéfalo/patologia
Encéfalo/virologia
Brasil
Calcinose/virologia
Feminino
Seguimentos
Seres Humanos
Lactente
Recém-Nascido
Masculino
Microcefalia/diagnóstico por imagem
Microcefalia/metabolismo
Microcefalia/virologia
Neuroimagem/métodos
Gravidez
Complicações Infecciosas na Gravidez/diagnóstico por imagem
Complicações Infecciosas na Gravidez/metabolismo
Complicações Infecciosas na Gravidez/virologia
Síndrome
Substância Branca/diagnóstico por imagem
Substância Branca/patologia
Substância Branca/virologia
Zika virus/imunologia
Infecção pelo Zika virus/congênito
Infecção pelo Zika virus/metabolismo
Infecção pelo Zika virus/virologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171015
[St] Status:MEDLINE
[do] DOI:10.1136/bmj.j4188


  9 / 4156 MEDLINE  
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[PMID]:28969387
[Au] Autor:Cavallin M; Rujano MA; Bednarek N; Medina-Cano D; Bernabe Gelot A; Drunat S; Maillard C; Garfa-Traore M; Bole C; Nitschké P; Beneteau C; Besnard T; Cogné B; Eveillard M; Kuster A; Poirier K; Verloes A; Martinovic J; Bidat L; Rio M; Lyonnet S; Reilly ML; Boddaert N; Jenneson-Liver M; Motte J; Doco-Fenzy M; Chelly J; Attie-Bitach T; Simons M; Cantagrel V; Passemard S; Baffet A; Thomas S; Bahi-Buisson N
[Ad] Endereço:Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Imagine Institute, Paris, France.
[Ti] Título:WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.
[So] Source:Brain;140(10):2597-2609, 2017 Oct 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.
[Mh] Termos MeSH primário: Fibroblastos/citologia
Microcefalia/genética
Microcefalia/patologia
Mitose/genética
Mutação/genética
Proteínas do Tecido Nervoso/genética
Células-Tronco Neurais/citologia
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Encéfalo/diagnóstico por imagem
Encéfalo/patologia
Células Cultivadas
Pré-Escolar
Drosophila
Proteínas de Drosophila/genética
Proteínas de Drosophila/metabolismo
Feminino
Fibroblastos/patologia
Regulação da Expressão Gênica/genética
Seres Humanos
Antígeno Ki-67/metabolismo
Masculino
Microcefalia/diagnóstico por imagem
Células-Tronco Neurais/patologia
Interferência de RNA/fisiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Ki-67 Antigen); 0 (Nerve Tissue Proteins); 0 (WDR81 protein, human)
[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/awx218


  10 / 4156 MEDLINE  
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[PMID]:28965845
[Au] Autor:Loviglio MN; Arbogast T; Jønch AE; Collins SC; Popadin K; Bonnet CS; Giannuzzi G; Maillard AM; Jacquemont S; Yalcin B; Katsanis N; Golzio C; Reymond A; 16p11.2 Consortium
[Ad] Endereço:Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
[Ti] Título:The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs.
[So] Source:Am J Hum Genet;101(4):564-577, 2017 Oct 05.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética
Transtorno Autístico/genética
Encéfalo/patologia
Transtornos Cromossômicos/genética
Cromossomos Humanos Par 16
Variações do Número de Cópias de DNA
Deficiência Intelectual/genética
Proteínas de Membrana/genética
Microcefalia/genética
Microcefalia/patologia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Proteínas Adaptadoras de Transdução de Sinal/fisiologia
Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Transtorno Autístico/imunologia
Transtorno Autístico/patologia
Encéfalo/metabolismo
Criança
Pré-Escolar
Deleção Cromossômica
Transtornos Cromossômicos/imunologia
Transtornos Cromossômicos/patologia
Cromossomos Humanos Par 16/genética
Cromossomos Humanos Par 16/imunologia
Estudos de Coortes
Embrião não Mamífero/metabolismo
Embrião não Mamífero/patologia
Feminino
Regulação da Expressão Gênica no Desenvolvimento
Seres Humanos
Lactente
Deficiência Intelectual/imunologia
Deficiência Intelectual/patologia
Masculino
Proteínas de Membrana/metabolismo
Proteínas de Membrana/fisiologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Meia-Idade
Fenótipo
Fosfoproteínas/fisiologia
Transdução de Sinais
Adulto Jovem
Peixe-Zebra/embriologia
Peixe-Zebra/genética
Proteínas de Peixe-Zebra/genética
Proteínas de Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (LAT protein, human); 0 (Lat protein, mouse); 0 (Membrane Proteins); 0 (Phosphoproteins); 0 (Zebrafish Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE



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