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1.
Rev Assoc Med Bras (1992) ; 65(6): 909-913, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31340324

RESUMO

INTRODUCTION: The Zika virus (ZIKV) is an arbovirus isolated for the first time in 1947 and transmitted to humans by the Aedes aegypti mosquito. In Brasil, it was first detected in May 2015. Since then, ZIKV has been identified as the etiological agent of acute exanthematous disease in Brasil, and Neuropediatricians of the Recife warned about an epidemic of microcephaly, and the Brazilian Ministry of Health confirmed the association between ZIKV and Congenital malformations and neurological syndromes. The eye, as an extension of the developing brain, has been examined in patients with microcephaly and maternal history of ZIKV infection. METHODS: Twenty newborn patients with microcephaly, whose mothers had presumed Zika virus during pregnancy, were analyzed through medical records. The nonparametric chi-square statistic was used to verify the association between head circumference and ocular alteration at a significance level of 0.0001. RESULTS: The significance of P = 0.000 in the value of non-parametric chi-square statistics was lower than the value of α = 0.0001, demonstrating that, at a level of 0.0001, there is an association between head circumference and ocular alteration. CONCLUSION: Although the knowledge of the natural evolution of the disease is still scarce, the current evidence is strong enough to establish a causal relationship between ZIKV infection during pregnancy and the increased incidence of the microcephaly and serious eye alterations that lead to the severe lower vision of these children.


Assuntos
Cefalometria , Oftalmopatias/virologia , Microcefalia/virologia , Infecção por Zika virus/complicações , Brasil , Oftalmopatias/patologia , Feminino , Cabeça/patologia , Humanos , Lactente , Masculino , Microcefalia/patologia , Valores de Referência
2.
Nat Commun ; 10(1): 2612, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197141

RESUMO

Primary microcephaly is caused by mutations in genes encoding centrosomal proteins including WDR62 and KIF2A. However, mechanisms underlying human microcephaly remain elusive. By creating mutant mice and human cerebral organoids, here we found that WDR62 deletion resulted in a reduction in the size of mouse brains and organoids due to the disruption of neural progenitor cells (NPCs), including outer radial glia (oRG). WDR62 ablation led to retarded cilium disassembly, long cilium, and delayed cell cycle progression leading to decreased proliferation and premature differentiation of NPCs. Mechanistically, WDR62 interacts with and promotes CEP170's localization to the basal body of primary cilium, where CEP170 recruits microtubule-depolymerizing factor KIF2A to disassemble cilium. WDR62 depletion reduced KIF2A's basal body localization, and enhanced KIF2A expression partially rescued deficits in cilium length and NPC proliferation. Thus, modeling microcephaly with cerebral organoids and mice reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly, disruption of which contributes to microcephaly.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Cinesina/metabolismo , Microcefalia/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas/metabolismo , Proteínas Repressoras/metabolismo , Animais , Técnicas de Cultura de Células , Proteínas de Ciclo Celular/genética , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Cílios/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/patologia , Neuroglia/citologia , Neuroglia/patologia , Organoides/patologia , Fosfoproteínas/genética , RNA Interferente Pequeno/metabolismo
3.
Int J Mol Sci ; 20(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035417

RESUMO

Glioblastoma multiforme and medulloblastoma are the most frequent high-grade brain tumors in adults and children, respectively. Standard therapies for these cancers are mainly based on surgical resection, radiotherapy, and chemotherapy. However, intrinsic or acquired resistance to treatment occurs almost invariably in the first case, and side effects are unacceptable in the second. Therefore, the development of new, effective drugs is a very important unmet medical need. A critical requirement for developing such agents is to identify druggable targets required for the proliferation or survival of tumor cells, but not of other cell types. Under this perspective, genes mutated in congenital microcephaly represent interesting candidates. Congenital microcephaly comprises a heterogeneous group of disorders in which brain volume is reduced, in the absence or presence of variable syndromic features. Genetic studies have clarified that most microcephaly genes encode ubiquitous proteins involved in mitosis and in maintenance of genomic stability, but the effects of their inactivation are particularly strong in neural progenitors. It is therefore conceivable that the inhibition of the function of these genes may specifically affect the proliferation and survival of brain tumor cells. Microcephaly genes encode for a few kinases, including CITK, PLK4, AKT3, DYRK1A, and TRIO. In this review, we summarize the evidence indicating that the inhibition of these molecules could exert beneficial effects on different aspects of brain cancer treatment.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Microcefalia/metabolismo , Microcefalia/patologia , Animais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Proteínas Serina-Treonina Quinases/metabolismo
4.
J Appl Oral Sci ; 27: e20180276, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31116278

RESUMO

OBJECTIVE: The aim of this study was to investigate possible malformations in the soft, bone and/or dental tissues in patients with congenital Zika Virus (ZIKV) by clinical and x-ray evaluation. METHODOLOGY: Thirty children born with ZIKV and 30 children born without ZIKV (control group) were included in the study. Patients were evaluated over 24 consecutive months according to the variables: sex, age, cleft palates, soft tissue lesions, alveolar ridge hyperplasia, short labial and lingual frenums, inadequate posture of the lingual and perioral muscles at rest, micrognathia, narrow palatine vaults, changes in the teeth shape and/or number, sequence eruption, spasms, seizures and eruption delay were evaluated. Chi-square test, Student's t-test and nominal logistic regression were used (p<0.05). RESULTS: Among the 30 babies examined, the mean age of the first dental eruption was 10.8±3.8 with almost two-thirds of the children (n=18, 60%) experiencing eruptions of their first tooth after 9 months of age, nine children (30%) had inadequate lingual posture at rest, more than half of the children (n=18, 60%) had short labial or lingual frenums. ZIKV babies showed a high prevalence of clef palate (p<0.001), inadequate lingual posture at rest (p=0.004), micrognathia (p=0.002), changes in the shape and/or number of teeth (p=0.006), alteration in sequence of dental eruption (p<0.001) and muscles spasms (p=0.002). The delay eruption was associated with inadequate lingual posture at rest (p=0.047), micrognathia (p=0.002) and changes in the shape and/or number of teeth (p=0.021). The delayed eruption (p=0.006) and narrow palatine vaults (p=0.008) were independently associated with ZIKV. Moreover, female patients showed the most narrow palatine vaults (p=0.010). CONCLUSIONS: The children with ZIKV showed a greater tendency to have delayed eruption of the first deciduous tooth, inadequate lingual posture and short labial and lingual frenums.


Assuntos
Anormalidades Dentárias/patologia , Anormalidades Dentárias/virologia , Infecção por Zika virus/congênito , Fatores Etários , Estudos de Casos e Controles , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Freio Labial/anormalidades , Freio Lingual/anormalidades , Modelos Logísticos , Masculino , Microcefalia/patologia , Microcefalia/fisiopatologia , Microcefalia/virologia , Análise Multivariada , Radiografia Dentária , Fatores de Tempo , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/fisiopatologia , Erupção Dentária/fisiologia , Infecção por Zika virus/fisiopatologia
5.
Gene ; 704: 97-102, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978478

RESUMO

In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.


Assuntos
Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Grupo com Ancestrais do Continente Asiático , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/deficiência , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Família , Feminino , Humanos , Índia , Lactente , Recém-Nascido , Hemorragias Intracranianas/congênito , Hemorragias Intracranianas/genética , Masculino , Microcefalia/patologia , Técnicas de Diagnóstico Molecular , Morte Perinatal , Convulsões/complicações , Convulsões/genética
6.
Top Magn Reson Imaging ; 28(1): 1-14, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30817674

RESUMO

In congenital Zika virus syndrome (CZS), the most frequent radiological findings are calcifications in the cortical-white matter junction and malformations of cortical development (pachygyria or polymicrogyria, which occur predominantly in the frontal lobes, or a simplified gyral pattern), ventriculomegaly, enlargement of the cisterna magna and the extra-axial subarachnoid space, corpus callosum abnormalities, and reduced brain volume. This syndrome can also result in a decrease in the brainstem and cerebellum volumes and delayed myelination. Infants with CZS may show venous thrombosis and lenticulostriate vasculopathies. Over a 3-year follow-up period, many infants with CZS showed hydrocephalus, reduction in brain calcifications, and greater reduction in brain thickness.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Diagnóstico por Imagem/métodos , Complicações Infecciosas na Gravidez/diagnóstico por imagem , Infecção por Zika virus/congênito , Infecção por Zika virus/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Calcinose/patologia , Calcinose/virologia , Feminino , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/patologia , Hidrocefalia/virologia , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Malformações do Sistema Nervoso/virologia , Gravidez , Síndrome , Tomografia Computadorizada por Raios X , Ultrassonografia Pré-Natal/métodos , Zika virus , Infecção por Zika virus/patologia
7.
J Hum Genet ; 64(5): 445-458, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30846821

RESUMO

Seckel syndrome (SS) is a rare spectrum of congenital severe microcephaly and dwarfism. One SS-causative gene is Ataxia Telangiectasia and Rad3-Related Protein (ATR), and ATR (c.2101 A>G) mutation causes skipping of exon 9, resulting in a hypomorphic ATR defect. This mutation is considered the cause of an impaired response to DNA replication stress, the main function of ATR, contributing to the pathogenesis of microcephaly. However, the precise behavior and impact of this splicing defect in human neural progenitor cells (NPCs) is unclear. To address this, we established induced pluripotent stem cells (iPSCs) from fibroblasts carrying the ATR mutation and an isogenic ATR-corrected counterpart iPSC clone. SS-patient-derived iPSCs (SS-iPSCs) exhibited cell type-specific splicing; exon 9 was dominantly skipped in fibroblasts and iPSC-derived NPCs, but it was included in undifferentiated iPSCs and definitive endodermal cells. SS-iPSC-derived NPCs (SS-NPCs) showed distinct expression profiles from ATR non-mutated NPCs with negative enrichment of neuronal genesis-related gene sets. In SS-NPCs, abnormal mitotic spindles occurred more frequently than in gene-corrected counterparts, and the alignment of NPCs in the surface of the neurospheres was perturbed. Finally, we tested several splicing-modifying compounds and found that TG003, a CLK1 inhibitor, could pharmacologically rescue the exon 9 skipping in SS-NPCs. Treatment with TG003 restored the ATR kinase activity in SS-NPCs and decreased the frequency of abnormal mitotic events. In conclusion, our iPSC model revealed a novel effect of the ATR mutation in mitotic processes of NPCs and NPC-specific missplicing, accompanied by the recovery of neuronal defects using a splicing rectifier.


Assuntos
Processamento Alternativo , Proteínas Mutadas de Ataxia Telangiectasia , Nanismo , Facies , Células-Tronco Pluripotentes Induzidas , Microcefalia , Modelos Biológicos , Mutação , Proteínas Mutadas de Ataxia Telangiectasia/biossíntese , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Nanismo/enzimologia , Nanismo/genética , Nanismo/patologia , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/enzimologia , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Microcefalia/enzimologia , Microcefalia/genética , Microcefalia/patologia
8.
Orphanet J Rare Dis ; 14(1): 38, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744660

RESUMO

BACKGROUND: The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A. RESULTS: In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication. CONCLUSIONS: With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.


Assuntos
Tubulina (Proteína)/genética , Adolescente , Criança , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Feminino , Genótipo , Humanos , Lisencefalia/genética , Lisencefalia/patologia , Masculino , Microcefalia/genética , Microcefalia/patologia , Mutação de Sentido Incorreto/genética , Fenótipo
9.
Nat Commun ; 10(1): 708, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755616

RESUMO

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.


Assuntos
Encefalopatias/genética , Microcefalia/genética , Valina-tRNA Ligase/genética , Alelos , Animais , Encefalopatias/enzimologia , Encefalopatias/patologia , Linhagem Celular , Modelos Animais de Doenças , Epilepsia/enzimologia , Epilepsia/genética , Epilepsia/patologia , Feminino , Fibroblastos , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Humanos , Mutação com Perda de Função , Masculino , Microcefalia/enzimologia , Microcefalia/patologia , Modelos Moleculares , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Prosencéfalo/patologia , Peixe-Zebra
10.
Artigo em Inglês | MEDLINE | ID: mdl-30678125

RESUMO

Zika virus (ZIKV) infection appeared in Brazil in 2015, causing an epidemic outbreak with increased rates of microcephaly and other serious birth disorders. We reviewed 102 cases of children who were diagnosed with microcephaly at birth and who had gestational exposure to ZIKV during the outbreak. We describe the clinical, neuroimaging, and neurophysiological findings. Most mothers (81%) reported symptoms of ZIKV infection, especially cutaneous rash, during the first trimester of pregnancy. The microcephaly was severe in 54.9% of the cases. All infants presented with brain malformations. The most frequent neuroimaging findings were cerebral atrophy (92.1%), ventriculomegaly (92.1%), malformation of cortical development (85.1%), and cortical⁻subcortical calcifications (80.2%). Abnormalities in neurological exams were found in 97.0% of the cases, epileptogenic activity in 56.3%, and arthrogryposis in 10.8% of the infants. The sensorineural screening suggested hearing loss in 17.3% and visual impairment in 14.1% of the infants. This group of infants who presented with microcephaly and whose mothers were exposed to ZIKV early during pregnancy showed clinical and radiological criteria for congenital ZIKV infection. A high frequency of brain abnormalities and signs of early neurological disorders were found, and epileptogenic activity and signs of sensorineural alterations were common. This suggests that microcephaly can be associated with a worst spectrum of neurological manifestations.


Assuntos
Microcefalia/patologia , Microcefalia/fisiopatologia , Infecção por Zika virus/congênito , Brasil/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Microcefalia/diagnóstico , Microcefalia/epidemiologia , Neuroimagem , Exame Neurológico , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/epidemiologia
11.
Nano Lett ; 19(4): 2215-2222, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30543300

RESUMO

Zika virus (ZIKV) has emerged as a global health threat due to its unexpected causal link to devastating neurological disorders such as fetal microcephaly; however, to date, no approved vaccine or specific treatment is available for ZIKV infection. Here we develop a biomimetic nanodecoy (ND) that can trap ZIKV, divert ZIKV away from its intended targets, and inhibit ZIKV infection. The ND, which is composed of a gelatin nanoparticle core camouflaged by mosquito medium host cell membranes, effectively adsorbs ZIKV and inhibits ZIKV replication in ZIKV-susceptible cells. Using a mouse model, we demonstrate that NDs significantly attenuate the ZIKV-induced inflammatory responses and degenerative changes and thus improve the survival rate of ZIKV-challenged mice. Moreover, by trapping ZIKV, NDs successfully prevent ZIKV from passing through physiologic barriers into the fetal brain and thereby mitigate ZIKV-induced fetal microcephaly in pregnant mice. We anticipate that this study will provide new insights into the development of safe and effective protection against ZIKV and various other viruses that threaten public health.


Assuntos
Microcefalia/prevenção & controle , Nanopartículas/administração & dosagem , Infecção por Zika virus/prevenção & controle , Zika virus/efeitos dos fármacos , Animais , Biomimética/métodos , Membrana Celular/efeitos dos fármacos , Membrana Celular/virologia , Culicidae/efeitos dos fármacos , Culicidae/virologia , Modelos Animais de Doenças , Feminino , Feto , Gelatina/administração & dosagem , Gelatina/química , Humanos , Camundongos , Microcefalia/patologia , Microcefalia/virologia , Nanopartículas/química , Gravidez , Zika virus/patogenicidade , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
12.
Proc Natl Acad Sci U S A ; 115(38): 9628-9633, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30185558

RESUMO

d-serine is a physiologic coagonist of NMDA receptors, but little is known about the regulation of its synthesis and synaptic turnover. The amino acid exchangers ASCT1 (Slc1a4) and ASCT2 (Slc1a5) are candidates for regulating d-serine levels. Using ASCT1 and ASCT2 KO mice, we report that ASCT1, rather than ASCT2, is a physiologic regulator of d-serine metabolism. ASCT1 is a major d-serine uptake system in astrocytes and can also export l-serine via heteroexchange, supplying neurons with the substrate for d-serine synthesis. ASCT1-KO mice display lower levels of brain d-serine along with higher levels of l-alanine, l-threonine, and glycine. Deletion of ASCT1 was associated with neurodevelopmental alterations including lower hippocampal and striatal volumes and changes in the expression of neurodevelopmental-relevant genes. Furthermore, ASCT1-KO mice exhibited deficits in motor function, spatial learning, and affective behavior, along with changes in the relative contributions of d-serine vs. glycine in mediating NMDA receptor activity. In vivo microdialysis demonstrated lower levels of extracellular d-serine in ASCT1-KO mice, confirming altered d-serine metabolism. These alterations are reminiscent of some of the neurodevelopmental phenotypes exhibited by patients with ASCT1 mutations. ASCT1-KO mice provide a useful model for potential therapeutic interventions aimed at correcting the metabolic impairments in patients with ASCT1 mutations.


Assuntos
Sistema ASC de Transporte de Aminoácidos/metabolismo , Encéfalo/fisiologia , Comunicação Celular/fisiologia , Microcefalia/genética , Serina/metabolismo , Sistema ASC de Transporte de Aminoácidos/genética , Animais , Astrócitos/fisiologia , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Modelos Animais de Doenças , Glicina/metabolismo , Células HEK293 , Humanos , Potenciação de Longa Duração/fisiologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcefalia/diagnóstico por imagem , Microcefalia/metabolismo , Microcefalia/patologia , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Neurônios/fisiologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia
13.
Proc Natl Acad Sci U S A ; 115(28): E6640-E6649, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946028

RESUMO

Endosomes have emerged as a central hub and pathogenic driver of Alzheimer's disease (AD). The earliest brain cytopathology in neurodegeneration, occurring decades before amyloid plaques and cognitive decline, is an expansion in the size and number of endosomal compartments. The strongest genetic risk factor for sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4). Previous studies have shown that ApoE4 potentiates presymptomatic endosomal dysfunction and defective endocytic clearance of amyloid beta (Aß), although how these two pathways are linked at a cellular and mechanistic level has been unclear. Here, we show that aberrant endosomal acidification in ApoE4 astrocytes traps the low-density lipoprotein receptor-related protein (LRP1) within intracellular compartments, leading to loss of surface expression and Aß clearance. Pathological endosome acidification is caused by ε4 risk allele-selective down-regulation of the Na+/H+ exchanger isoform NHE6, which functions as a critical leak pathway for endosomal protons. In vivo, the NHE6 knockout (NHE6KO) mouse model showed elevated Aß in the brain, consistent with a causal effect. Increased nuclear translocation of histone deacetylase 4 (HDAC4) in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 allele, suggested a mechanistic basis for transcriptional down-regulation of NHE6. HDAC inhibitors that restored NHE6 expression normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, and amyloid clearance. Thus, NHE6 is a downstream effector of ApoE4 and emerges as a promising therapeutic target in AD. These observations have prognostic implications for patients who have Christianson syndrome with loss of function mutations in NHE6 and exhibit prominent glial pathology and progressive hallmarks of neurodegeneration.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Endossomos/metabolismo , Epigênese Genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Apolipoproteína E4/genética , Astrócitos/patologia , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Endossomos/genética , Endossomos/patologia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Camundongos , Camundongos Knockout , Microcefalia/tratamento farmacológico , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/patologia , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/metabolismo , Transtornos da Motilidade Ocular/patologia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
14.
J Radiol Case Rep ; 12(3): 18-27, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29875990

RESUMO

We report the imaging appearances of a case of pathologically proven, neonatal neuroblastoma 4S with diffuse hepatic metastatic involvement at presentation. Patient had an abnormal appearing liver both by ultrasound and MR. There was no evidence for associated adrenal tumor by imaging. Lack of an associated adrenal mass led to initial misinterpretation of diffuse hepatic accumulation of MIBG seen with radionuclide scintigraphy. To the best our knowledge, this is the first report of metastatic neonatal 4S neuroblastoma without an adrenal (or extra-adrenal) primary identified either on pre- or post-natal imaging.


Assuntos
Neoplasias Encefálicas/patologia , Dedos/anormalidades , Deficiência Intelectual/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Microcefalia/patologia , Hipotonia Muscular/patologia , Miopia/patologia , Neuroblastoma/secundário , Obesidade/patologia , 3-Iodobenzilguanidina , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/análise , Biópsia , Neoplasias Encefálicas/tratamento farmacológico , Meios de Contraste , Deficiências do Desenvolvimento/patologia , Diagnóstico Diferencial , Feminino , Dedos/patologia , Humanos , Recém-Nascido , Neoplasias Hepáticas/tratamento farmacológico , Imagem por Ressonância Magnética , Estadiamento de Neoplasias , Neuroblastoma/tratamento farmacológico , Compostos Organometálicos , Degeneração Retiniana , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X
15.
Nature ; 556(7701): 370-375, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29643508

RESUMO

The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding. However, the evolutionary mechanisms that drive cortical size and structure are unknown. Although genes that are essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (a disorder associated with reduced brain size and intellectual disability) 1 , studies of these genes in mice, which have a smooth cortex that is one thousand times smaller than the cortex of humans, have provided limited insight. Mutations in abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by at least 50% in humans2-4, but have little effect on the brains of mice5-9; this probably reflects evolutionarily divergent functions of ASPM10,11. Here we used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity12-14 than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25-40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients3,4, suggesting that loss of 'cortical units' has occurred. The cortex of fetal Aspm knockout ferrets displays a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates12-16. These data suggest an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor.


Assuntos
Evolução Biológica , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/metabolismo , Furões , Deleção de Genes , Microcefalia/genética , Microcefalia/patologia , Proteínas do Tecido Nervoso/deficiência , Sequência de Aminoácidos , Animais , Proteínas de Ligação a Calmodulina/deficiência , Proteínas de Ligação a Calmodulina/metabolismo , Centrossomo/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Furões/anatomia & histologia , Furões/genética , Edição de Genes , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Mutação em Linhagem Germinativa , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Tamanho do Órgão , Transcrição Genética
16.
Cytogenet Genome Res ; 154(4): 201-208, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29656294

RESUMO

Ring chromosome 6, r(6), is an extremely rare cytogenetic abnormality with clinical heterogeneity which arises typically de novo. The phenotypes of r(6) can be highly variable, ranging from almost normal to severe malformations and neurological defects. Up to now, only 33 cases have been reported in the literature. In this 10-year follow-up study, we report a case presenting distinctive facial features, severe developmental delay, and gray matter heterotopia with r(6) and terminal deletions of 6p25.3 (115426-384174, 268 kb) and 6q26-27 (168697778-170732033, 2.03 Mb) encompassing 2 and 15 candidate genes, respectively, which were detected using G-banding karyotyping, FISH, and chromosomal microarray analysis. We also analyzed the available information on the clinical features of the reported r(6) cases in order to provide more valuable information on genotype-phenotype correlations. To the best of our knowledge, this is the first report of gray matter heterotopia manifested in a patient with r(6) in China, and the deletions of 6p and 6q in our case are the smallest with the precise size of euchromatic material loss currently known.


Assuntos
Cromossomos Humanos Par 6/genética , Deficiências do Desenvolvimento/genética , Face/anormalidades , Substância Cinzenta/patologia , Deficiência Intelectual/genética , Microcefalia/genética , Cromossomos em Anel , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Microcefalia/patologia , Pessoa de Meia-Idade
17.
Nat Commun ; 9(1): 1352, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29636449

RESUMO

Feingold syndrome is a skeletal dysplasia caused by loss-of-function mutations of either MYCN (type 1) or MIR17HG that encodes miR-17-92 microRNAs (type 2). Since miR-17-92 expression is transcriptionally regulated by MYC transcription factors, it has been postulated that Feingold syndrome type 1 and 2 may be caused by a common molecular mechanism. Here we show that Mir17-92 deficiency upregulates TGF-ß signaling, whereas Mycn-deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-ß signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-ß signaling is responsible for the skeletal defect of Feingold syndrome type 2. By contrast, the skeletal phenotype of Mycn-deficiency is partially rescued by Pten heterozygosity, but not by TGF-ß inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2.


Assuntos
Pálpebras/anormalidades , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , MicroRNAs/genética , Microcefalia/genética , Proteína Proto-Oncogênica N-Myc/genética , Transdução de Sinais/genética , Fístula Traqueoesofágica/genética , Animais , Modelos Animais de Doenças , Pálpebras/metabolismo , Pálpebras/patologia , Feminino , Regulação da Expressão Gênica , Heterozigoto , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Deformidades Congênitas dos Membros/metabolismo , Deformidades Congênitas dos Membros/patologia , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Microcefalia/metabolismo , Microcefalia/patologia , Proteína Proto-Oncogênica N-Myc/deficiência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fístula Traqueoesofágica/metabolismo , Fístula Traqueoesofágica/patologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
18.
J Hum Genet ; 63(1): 19-25, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29215095

RESUMO

We ascertained two unrelated consanguineous families with two affected children each having microcephaly, refractory seizures, intellectual disability, and spastic quadriparesis. Magnetic resonance imaging showed atrophy of cerebrum, cerebellum and spinal cord, prominent cisterna magna, symmetric T2 hypo-intensities in the bilateral basal ganglia and thinning of corpus callosum. Whole-exome sequencing of three affected individuals revealed c.105C>A [p.(Tyr35Ter)] variant in AIMP2. The variant lies in a common homozygous region of 940 kb on chromosome 7 and is likely to have been inherited from a common ancestor. The phenotype noted in our subjects' shares marked similarity with that of hypomyelinating leukodystrophy-3 caused by mutations in closely related gene AIMP1. We hereby report the first human disease associated with deleterious mutations in AIMP2.


Assuntos
Códon sem Sentido , Doenças Genéticas Inatas/genética , Homozigoto , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Quadriplegia/genética , Convulsões/genética , Criança , Cromossomos Humanos Par 7/genética , Exoma , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Microcefalia/patologia , Transtornos do Neurodesenvolvimento/patologia , Quadriplegia/patologia , Convulsões/patologia
19.
Semin Cell Dev Biol ; 76: 76-85, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28912110

RESUMO

Primary microcephaly (PM) refers to a congenitally small brain, resulting from insufficient prenatal production of neurons, and serves as a model disease for brain volumic development. Known PM genes delineate several cellular pathways, among which the centriole duplication pathway, which provide interesting clues about the cellular mechanisms involved. The general interest of the genetic dissection of PM is illustrated by the convergence of Zika virus infection and PM gene mutations on congenital microcephaly, with CENPJ/CPAP emerging as a key target. Physical (protein-protein) and genetic (digenic inheritance) interactions of Wdr62 and Aspm have been demonstrated in mice, and should now be sought in humans using high throughput parallel sequencing of multiple PM genes in PM patients and control subjects, in order to categorize mutually interacting genes, hence delineating functional pathways in vivo in humans.


Assuntos
Encéfalo/patologia , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Humanos , Microcefalia/patologia , Mutação , Malformações do Sistema Nervoso/patologia
20.
Congenit Anom (Kyoto) ; 58(1): 16-23, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28464341

RESUMO

Environmental enrichment (EE) mediates recovery from sensory, motor, and cognitive deficits and emotional abnormalities. In the present study, we examined the effects of EE on locomotor activity and neuronal activity in the amygdala in control and methylazoxymethanol acetate (MAM)-induced micrencephalic rats after challenge in a novel open field. Control rats housed in EE (CR) showed reduced locomotor activity compared to rats housed in a conventional cage (CC), whereas hyperactivity was seen in MAM rats housed in a conventional cage (MC) and in MAM rats housed in EE (MR). Novel open field exposure in both CC and MC resulted in a marked increase in Fos expression in the anterior and posterior parts of the basolateral amygdaloid nucleus, basomedial nucleus, and medial nucleus, whereas these increases in expression were not observed in CR. The effect of EE on Fos expression in the amygdala was different in MR exposed to a novel open field compared to CR. Furthermore, we observed a quite different pattern of Fos expression in the central nucleus of the amygdala between control and MAM rats. The present results suggest that neuronal activity in the amygdala that responds to anxiety is altered in MAM rats, especially when the rats are reared in EE. These alterations may cause behavioral differences between control and MAM rats.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Meio Ambiente , Comportamento Exploratório , Locomoção , Microcefalia/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Animais , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Acetato de Metilazoximetanol/toxicidade , Microcefalia/induzido quimicamente , Microcefalia/genética , Microcefalia/patologia , Neurotoxinas/toxicidade , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley
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