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1.
Nat Rev Mol Cell Biol ; 22(2): 96-118, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33353982

RESUMO

Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.


Assuntos
Regulação da Expressão Gênica , Doenças do Sistema Imunitário/patologia , Neoplasias/patologia , Transtornos do Neurodesenvolvimento/patologia , RNA Longo não Codificante/genética , Animais , Humanos , Doenças do Sistema Imunitário/genética , Neoplasias/genética , Transtornos do Neurodesenvolvimento/genética , Transdução de Sinais
2.
Neuron ; 107(6): 1000-1013, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32970995

RESUMO

Human organoid models of the central nervous system, including the neural retina, are providing unprecedented opportunities to explore human neurodevelopment and neurodegeneration in controlled culture environments. In this Perspective, we discuss how the single-cell multi-omic toolkit has been used to identify features and limitations of brain and retina organoids and how these tools can be deployed to study congenital brain malformations and vision disorders in organoids. We also address how to improve brain and retina organoid protocols to revolutionize in vitro disease modeling.


Assuntos
Genômica/métodos , Transtornos do Neurodesenvolvimento/metabolismo , Organoides/metabolismo , Cultura Primária de Células/métodos , Análise de Célula Única/métodos , Transtornos da Visão/metabolismo , Humanos , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Organoides/crescimento & desenvolvimento , Organoides/patologia , Transtornos da Visão/genética , Transtornos da Visão/patologia
3.
Am J Hum Genet ; 107(3): 555-563, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758449

RESUMO

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtorno do Espectro Autista/patologia , Criança , Metilação de DNA/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epigênese Genética/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Transcriptoma/genética
4.
Am J Hum Genet ; 107(3): 499-513, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32721402

RESUMO

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.


Assuntos
Carcinogênese/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Transtornos do Neurodesenvolvimento/genética , Síndrome de Noonan/genética , Pré-Escolar , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/patologia , Síndrome de Noonan/fisiopatologia , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Transdução de Sinais , Sequenciamento Completo do Exoma , Proteínas ras/genética
5.
Nat Commun ; 11(1): 3358, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620757

RESUMO

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.


Assuntos
Córtex Cerebral/patologia , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Mapeamento Encefálico , Córtex Cerebral/citologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/patologia , Neuroimagem , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Análise Espacial , Adulto Jovem
6.
Nat Commun ; 11(1): 2755, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488011

RESUMO

Fragile X Syndrome results from a loss of Fragile X Mental Retardation Protein (FMRP). We now show that FMRP is a member of a Cav3-Kv4 ion channel complex that is known to regulate A-type potassium current in cerebellar granule cells to produce mossy fiber LTP. Mossy fiber LTP is absent in Fmr1 knockout (KO) mice but is restored by FMRP(1-297)-tat peptide. This peptide further rapidly permeates the blood-brain barrier to enter cells across the cerebellar-cortical axis that restores the balance of protein translation for at least 24 h and transiently reduces elevated levels of activity of adult Fmr1 KO mice in the Open Field Test. These data reveal that FMRP(1-297)-tat can improve function from the levels of protein translation to synaptic efficacy and behaviour in a model of Fragile X syndrome, identifying a potential therapeutic strategy for this genetic disorder.


Assuntos
Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Canais Iônicos/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Masculino , Camundongos , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Biossíntese de Proteínas
7.
Lancet Diabetes Endocrinol ; 8(7): 594-605, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32559475

RESUMO

BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.


Assuntos
Biomarcadores/análise , Transtornos Mentais/patologia , Transportadores de Ácidos Monocarboxílicos/deficiência , Doenças Musculares/patologia , Transtornos do Neurodesenvolvimento/patologia , Simportadores/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Agências Internacionais , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , Doenças Musculares/etiologia , Mutação , Transtornos do Neurodesenvolvimento/etiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Simportadores/genética , Adulto Jovem
8.
Adv Exp Med Biol ; 1195: 35-41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468456

RESUMO

Human brain possesses a unique anatomy and physiology. For centuries, methodological barriers and ethical challenges in accessing human brain tissues have restricted researchers into using 2-D cell culture systems and model organisms as a tool for investigating the mechanisms underlying neurological disorders in humans. However, our understanding regarding the human brain development and diseases has been recently extended due to the generation of 3D brain organoids, grown from human stem cells or induced pluripotent stem cells (iPSCs). This system evolved into an attractive model of brain diseases as it recapitulates to a great extend the cellular organization and the microenvironment of a human brain. This chapter focuses on the application of brain organoids in modelling several neurodevelopmental and neurodegenerative diseases.


Assuntos
Encéfalo/patologia , Doenças Neurodegenerativas/patologia , Transtornos do Neurodesenvolvimento/patologia , Organoides/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/patologia
9.
Am J Physiol Cell Physiol ; 318(6): C1264-C1283, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320288

RESUMO

Plasticity within the neuronal networks of the brain underlies the ability to learn and retain new information. The initial discovery of synaptic plasticity occurred by measuring synaptic strength in vivo, applying external stimulation and observing an increase in synaptic strength termed long-term potentiation (LTP). Many of the molecular pathways involved in LTP and other forms of synaptic plasticity were subsequently uncovered in vitro. Over the last few decades, technological advances in recording and imaging in live animals have seen many of these molecular mechanisms confirmed in vivo, including structural changes both pre- and postsynaptically, changes in synaptic strength, and changes in neuronal excitability. A well-studied aspect of neuronal plasticity is the capacity of the brain to adapt to its environment, gained by comparing the brains of deprived and experienced animals in vivo, and in direct response to sensory stimuli. Multiple in vivo studies have also strongly linked plastic changes to memory by interfering with the expression of plasticity and by manipulating memory engrams. Plasticity in vivo also occurs in the absence of any form of external stimulation, i.e., during spontaneous network activity occurring with brain development. However, there is still much to learn about how plasticity is induced during natural learning and how this is altered in neurological disorders.


Assuntos
Encéfalo/metabolismo , Sinapses Elétricas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Transmissão Sináptica , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Sinapses Elétricas/patologia , Aprendizagem , Potenciação de Longa Duração , Modelos Neurológicos , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/patologia , Potenciais Sinápticos
10.
PLoS Genet ; 16(4): e1008653, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32324743

RESUMO

Neural stem cells (NSCs) are crucial for development, regeneration, and repair of the nervous system. Most NSCs in mammalian adult brains are quiescent, but in response to extrinsic stimuli, they can exit from quiescence and become reactivated to give rise to new neurons. The delicate balance between NSC quiescence and activation is important for adult neurogenesis and NSC maintenance. However, how NSCs transit between quiescence and activation remains largely elusive. Here, we discuss our current understanding of the molecular mechanisms underlying the reactivation of quiescent NSCs. We review recent advances on signaling pathways originated from the NSC niche and their crosstalk in regulating NSC reactivation. We also highlight new intrinsic paradigms that control NSC reactivation in Drosophila and mammalian systems. We also discuss emerging evidence on modeling human neurodevelopmental disorders using NSCs.


Assuntos
Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Transdução de Sinais , Animais , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Humanos , Insulina/metabolismo , Transtornos do Neurodesenvolvimento/terapia , Nicho de Células-Tronco
11.
Proc Natl Acad Sci U S A ; 117(12): 6836-6843, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32144139

RESUMO

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.


Assuntos
Canais de Cálcio/genética , Córtex Motor/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas/genética , Proteínas com Domínio T/genética , Córtex Visual/fisiopatologia , Adulto , Idoso , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Mapeamento Encefálico , Estudos de Coortes , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Desempenho Psicomotor , Percepção Visual
12.
Int Rev Neurobiol ; 150: 17-40, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32204831

RESUMO

The impact of stress on brain health begins in the womb. Both animal and human studies have found that prenatal maternal stress affects the brain and behavior of the offspring. Stressful life events, exposure to a natural disaster, and symptoms of maternal anxiety and depression increase the risk for the child having a range of emotional, behavioral and/or cognitive problems in later life. These include depression, anxiety, Attention Deficit Hyperactivity Disorder (ADHD), and/or conduct disorders. There is an increased risk for other outcomes also, including preterm delivery and reduced telomere length, possibly indicative of an accelerated life history. The causal role of prenatal maternal stress on the etiology of the neurodevelopmental disorders is supported by large population cohorts, which have controlled for a wide range of potential confounders, including postnatal maternal mood. More recently, research has begun to explore the biological correlates and mediators of these findings. These studies suggest that the hypothalamic pituitary adrenal (HPA) axis plays a role in mediating the effects of maternal stress on the fetal brain. Further, in vivo brain imaging research reports that maternal stress is associated with changes in limbic and frontotemporal networks, and the functional and microstructural connections linking them. The structural changes include cortical thinning and an enlarged amygdala. While these studies have been conducted on smaller sample sizes and could not control for many confounders, the observed brain changes do plausibly underlie many of the emotional, behavioral and cognitive changes found to be associated with prenatal stress.


Assuntos
Tonsila do Cerebelo , Córtex Cerebral , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário , Transtornos Mentais , Transtornos do Neurodesenvolvimento , Neuroimagem , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/patologia , Animais , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Criança , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Transtornos Mentais/fisiopatologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia
13.
BMC Med Genet ; 21(1): 59, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209057

RESUMO

BACKGROUND: Intellectual disability (ID) is both a clinically diverse and genetically heterogeneous group of disorder, with an onset of cognitive impairment before the age of 18 years. ID is characterized by significant limitations in intellectual functioning and adaptive behaviour. The identification of genetic variants causing ID and neurodevelopmental disorders using whole-exome sequencing (WES) has proven to be successful. So far more than 1222 primary and 1127 candidate genes are associated with ID. METHODS: To determine pathogenic variants causative of ID in three unrelated consanguineous Pakistani families, we used a combination of WES, homozygosity-by-descent mapping, de-deoxy sequencing and bioinformatics analysis. RESULTS: Rare pathogenic single nucleotide variants identified by WES which passed our filtering strategy were confirmed by traditional Sanger sequencing and segregation analysis. Novel and deleterious variants in VPS53, GLB1, and MLC1, genes previously associated with variable neurodevelopmental anomalies, were found to segregate with the disease in the three families. CONCLUSIONS: This study expands our knowledge on the molecular basis of ID as well as the clinical heterogeneity associated to different rare genetic causes of neurodevelopmental disorders. This genetic study could also provide additional knowledge to help genetic assessment as well as clinical and social management of ID in Pakistani families.


Assuntos
Consanguinidade , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Polimorfismo Genético , Proteínas de Transporte Vesicular/genética , beta-Galactosidase/genética , Criança , Pré-Escolar , Família , Feminino , Genes Recessivos/genética , Heterogeneidade Genética , Testes Genéticos , Homozigoto , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Masculino , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Paquistão/epidemiologia , Linhagem , Sequenciamento Completo do Exoma
14.
Neuron ; 106(3): 404-420.e8, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32135084

RESUMO

De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.


Assuntos
Córtex Cerebral/metabolismo , RNA Helicases DEAD-box/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Neurogênese , Animais , Linhagem Celular Tumoral , Células Cultivadas , Córtex Cerebral/anormalidades , Córtex Cerebral/embriologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/patologia , RNA/metabolismo
15.
Rev. psiquiatr. infanto-juv ; 37(1): 5-16, ene.-mar. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-193560

RESUMO

INTRODUCCIÓN: La escala CBCL de Achenbach completada por padres evalúa un amplio rango de problemas conductuales y emocionales de inicio en la infancia. Sus subescalas "retraimiento-depresión" y principalmente "problemas de pensamiento" se han propuesto como medida de detección de riesgo de psicosis en adolescentes. Dentro de los posibles endofenotipos de la esquizofrenia se plantean la disfunción ejecutiva y la alteración en el lenguaje pragmático. OBJETIVOS: Identificar mediante ambas subescalas de la CBCL un subgrupo de niños y adolescentes con puntuaciones elevadas entre los pacientes que consultan en psiquiatría infantil por trastornos del neurodesarrollo y que tienen antecedentes familiares de esquizofrenia. MATERIAL Y MÉTODOS: Los padres completan la escala CBCL de Achenbach, CCC-Childrens Communication Checklist- (evaluación del lenguaje pragmático) y BRIEF-2 (evaluación conductual de la función ejecutiva). RESULTADOS: Se incluyeron 21 niños (16 niños: 5 niñas). Edad media 11,4 años. Los diagnósticos principales fueron TDAH (66,7%), trastorno de aprendizaje (9,5%) y TEA (9,5%). Las dos subescalas de la CBCL "retraimiento-depresión" y "problemas de pensamiento" discriminan dos grupos, uno con afectación (n=11) con puntuaciones por encima del Pc70 y otro sin afectación (n=10) con puntuaciones inferiores al Pc70. Los casos con afectación mostraron más dificultades en el lenguaje pragmático y función ejecutiva que los del grupo sin afectación. CONCLUSIONES: Realizar una evaluación dimensional más completa de la psicopatología, como la que ofrece la CBCL, en niños con trastornos del neurodesarrollo y antecedentes familiares de esquizofrenia puede ayudar a describir mejor las dificultades premórbidas e identificar casos susceptibles de seguimiento longitudinal e intervención precoz


INTRODUCTION: The CBCL is a standardized form that parents fill out to describe their children ́s behavioral and emotional problems. Previous studies have suggested that two subscales, "withdrawal-depressed" and mainly "thought problems" may have utility as a psychosis risk screening measure in youth. Executive function and higher-order language dysfunctions have been postulated as potential endophenotypes for schizophrenia. OBJECTIVES: To identify by means of the two CBCL subscales mentioned above, a group of children and adolescents with higher ratings amongst those patients attending an outpatient psychiatric clinic, who present a neurodevelopmental disorder and a family history of schizophrenia MATERIAL AND METHODS: Parents filled out CBCL, CCC-Childrens Communication Checklist- (evaluates pragmatic language) and BRIEF-2 (Behavior Rating Inventory of Executive Function). RESULTS: Twenty-one children were included (16 males; 5 females). Mean age 11,4 y/o. Main diagnoses were ADHD (66,7%), Learning Disorder (9,5%) and ASD (9,5%). CBCL subscales "withdrawn-depressed" and "thought problems" discriminated two groups. One with higher ratings (above Pc70) showing the presence of symptoms (n=11) and the other with lower ratings (below Pc70) indicating symptom absence (n=10). The first group showed more pragmatic language difficulties as well as poorer executive function. CONCLUSIONS: A more comprehensive dimensional evaluation of the psychopathology of children with neurodevelopmental disorders and family history of schizophrenia, by means of CBCL, may provide a better description of premorbid difficulties, helping to identify more vulnerable cases for long term follow up and early intervention


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Função Executiva , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/psicologia , Esquizofrenia/fisiopatologia , Anamnese , Psicopatologia/métodos , Estudos Transversais , Transtornos da Comunicação , Deficiências da Aprendizagem
16.
Am J Hum Genet ; 106(2): 246-255, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004447

RESUMO

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Proteínas Ativadoras de GTPase/genética , Hipotonia Muscular/etiologia , Mutação , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/etiologia , Espasmos Infantis/etiologia , Alelos , Movimento Celular , Proliferação de Células , Pré-Escolar , Família , Transtornos da Alimentação e da Ingestão de Alimentos/patologia , Feminino , Humanos , Lactente , Masculino , Hipotonia Muscular/patologia , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Espasmos Infantis/patologia
17.
PLoS One ; 15(2): e0229434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32109947

RESUMO

The main goal of this manuscript was to investigate the neurodevelopment of children exposed by Zika virus in the intrauterine period who are asymptomatic at birth. Newborns with documented Zika virus exposure during the intrauterine period who were asymptomatic at birth were followed in the first two years of life for neurodevelopment using Bayley III test. Children were classified as having normal or delayed neurodevelopment for age based on most recent Bayley III evaluation results. Eighty-four infants were included in the study. The first Bayley III evaluation was performed at a mean chronological age of 9.7±3.1 month; 13 children (15%) had a delay in one of the three domains, distributed as follow: 10 (12%) in the language domain and 3 (3.5%) in the motor domain. The most recent Bayley III evaluation was performed at a mean age 15.3±3.1 months; 42 children (50%) had a delay in one of the three domains: 4 (5%) in cognition, 31 (37%) in language, and 20 (24%) in motor performance. There were no statistical differences in Gender, Gestational Age, Birth Weight and Head Circurference at birth between children with normal and delayed neurodevelopment for age. A very high proportion of children exposed ZIKV during pregnancy who were asymptomatic at birth demonstrated a delay in neurodevelopment, mainly in the language domain, the first two years of life.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Complicações Infecciosas na Gravidez/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Útero/virologia , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Adolescente , Adulto , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/patologia , Parto , Gravidez , Complicações Infecciosas na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Adulto Jovem , Infecção por Zika virus/virologia
18.
Int J Mol Sci ; 21(2)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31941109

RESUMO

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent years. A wealth of data show that 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows the rescue of long-term potentiation (LTP) and long-term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, modulates the function of immune cells, and is likely to play a role in the gut-brain axis. In this review, we will mainly focus on recent findings on this receptor's role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gastrointestinal (GI) tract and immune system.


Assuntos
Encéfalo/imunologia , Enteropatias/imunologia , Potenciação de Longa Duração/imunologia , Depressão Sináptica de Longo Prazo/imunologia , Transtornos Mentais/imunologia , Transtornos do Neurodesenvolvimento/imunologia , Receptores de Serotonina/imunologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Enteropatias/patologia , Intestinos/imunologia , Intestinos/patologia , Transtornos Mentais/patologia , Transtornos do Neurodesenvolvimento/patologia
19.
J Clin Invest ; 130(2): 813-826, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904590

RESUMO

Multipass membrane proteins have a myriad of functions, including transduction of cell-cell signals, ion transport, and photoreception. Insertion of these proteins into the membrane depends on the endoplasmic reticulum (ER) membrane protein complex (EMC). Recently, birth defects have been observed in patients with variants in the gene encoding a member of this complex, EMC1. Patient phenotypes include congenital heart disease, craniofacial malformations, and neurodevelopmental disease. However, a molecular connection between EMC1 and these birth defects is lacking. Using Xenopus, we identified defects in neural crest cells (NCCs) upon emc1 depletion. We then used unbiased proteomics and discovered a critical role for emc1 in WNT signaling. Consistent with this, readouts of WNT signaling and Frizzled (Fzd) levels were reduced in emc1-depleted embryos, while NCC defects could be rescued with ß-catenin. Interestingly, other transmembrane proteins were mislocalized upon emc1 depletion, providing insight into additional patient phenotypes. To translate our findings back to humans, we found that EMC1 was necessary for human NCC development in vitro. Finally, we tested patient variants in our Xenopus model and found the majority to be loss-of-function alleles. Our findings define molecular mechanisms whereby EMC1 dysfunction causes disease phenotypes through dysfunctional multipass membrane protein topogenesis.


Assuntos
Retículo Endoplasmático/metabolismo , Membranas Intracelulares/metabolismo , Complexos Multiproteicos/metabolismo , Crista Neural/embriologia , Transtornos do Neurodesenvolvimento/metabolismo , Via de Sinalização Wnt , Proteínas de Xenopus/metabolismo , Animais , Modelos Animais de Doenças , Retículo Endoplasmático/genética , Retículo Endoplasmático/patologia , Membranas Intracelulares/patologia , Complexos Multiproteicos/genética , Crista Neural/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Xenopus , Proteínas de Xenopus/genética
20.
Eur J Med Genet ; 63(1): 103611, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30615951

RESUMO

Xia-Gibbs syndrome is a rare genetic condition characterized by intellectual disability, growth retardation, delayed psychomotor development with absent or poor expressive language, distinctive facial features, hypotonia, laryngomalacia and obstructive sleep apnea. At present, Xia-Gibbs syndrome has been reported to be mainly caused by truncating mutations in AHDC1 gene located on chromosome 1p36.11. However, the evidence supporting AHDC1 deletion as a cause of this syndrome is still limited. Here we report an 8-year-old boy carrying a de novo 575 Kb microdeletion at 1p36.11 including AHDC1 gene. The boy is characterized by intellectual disability, developmental delay, short stature, expressive language delay, facial dysmorphism, obstructive sleep apnea and multiple congenital anomalies, which are mostly consistent with the characteristics of Xia-Gibbs syndrome. Therefore, we provide further supporting evidence that AHDC1 deletion causes Xia-Gibbs syndrome through a haploinsufficiency mechanism. Currently, clinical consequences of AHDC1 gene duplication has never been reported. Here, we identify a de novo 480 Kb duplication at 1p36.11p35.3 spanning the entire AHDC1 gene in a 2-year-8-month boy, who displays similar clinical features with that of Xia-Gibbs syndrome, in particular, expressive language delay, hypotonia, laryngomalacia and obstructive sleep apnea, as well as mirrored phenotypes such as overgrowth and advanced bone age. WES test excludes to the degree possible other known genetic causes. This case suggests that AHDC1 gene duplication may be clinical significance.


Assuntos
Deleção Cromossômica , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Transtornos do Neurodesenvolvimento/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Deficiências do Desenvolvimento/patologia , Duplicação Gênica/genética , Haploinsuficiência/genética , Humanos , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo
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