Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 815
Filtrar
1.
An Acad Bras Cienc ; 91(3): e20180882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553368

RESUMO

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by dynamic mutations of a CGG repetition segment in an X chromosome's single gene. It is considered the leading hereditary cause of both Autism Spectrum Disorders and Intellectual Disability. Some authors suggest that all individuals diagnosed with some of these latter conditions to be clinically and molecularly trialled for FXS due to the high levels of comorbidity between both conditions and also due to the variable expressiveness of this syndrome. This study has focused on verifying the presence of FMR1 expanded alleles since there is a lack of information about this kind of mutation in autism patients from the northern region of Brazil. The presence of large alleles for this gene could offer new therapeutic or pharmacological methods for the treatment of these patients. Both the presence and the frequency of CGG expansions were verified in 90 autism males by molecular analysis. Four of them had intermediate alleles and four others presented premutated alleles. Premutation carriers are on the propensity of developing the late onset Fragile X-associated tremor/ataxia syndrome. No full mutation alleles were found. Further studies are necessary to obtain more accurate statistical data about this kind of dynamic mutation.


Assuntos
Transtorno do Espectro Autista/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mutação/genética , Adolescente , Alelos , Criança , Pré-Escolar , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Adulto Jovem
2.
Artigo em Russo | MEDLINE | ID: mdl-31317896

RESUMO

AIM: Long continuous stretches of homozygosity (LCSH) are regularly detected in studies using molecular karyotyping (SNP array). Despite this type of variation being able to provide meaningful data on the parents' kinship, uniparental disomy and chromosome rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Despite their direct relationship to imprinting, LCSH in imprinted loci have not been considered in terms of pathogenicity. The present work is aimed at studying LCSH in chromosomal regions containing imprinted genes previously associated with disease in children with idiopathic intellectual disability, autism, congenital malformations and/or epilepsy. MATERIAL AND METHODS: Five hundred and four patients with autism spectrum disorders and intellectual disability were examined. RESULTS: LCSH affecting imprinted loci associated with various diseases were identified in 40 (7.9%) individuals. Chromosomal region 7q21.3 was affected in twenty three cases, 15q11.2 in twelve, 11p15.5 in five, 7q32.2 in four. Four patients had 2 LCSH affecting imprinted loci. Besides one LCSH in 7q31.33q32.3 (~4 Mbp) region, all LCSH were 1-1.6 Mbp. Clinically, these cases resembled the corresponding imprinting diseases (e.g. Silver-Russell, Beckwith-Wiedemann, Prader-Willi, Angelman syndromes). Parental kinship was identified in 8 cases (1.59%), which were not affected by LCSH at imprinted loci. CONCLUSION: The present study shows that LCSH affecting chromosomal regions 7q21.3, 7q32.2, 11p15.5 and 15p11.2 occur in about 7.9% of children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations is obviously common in a group of children with neurodevelopmental disorders. LCSH less than 2.5-10 Mbp are usually ignored in molecular karyotyping (SNP array) studies and, therefore, an important epigenetic cause of intellectual disability, autism or epilepsy with high probability remains without attention.


Assuntos
Síndrome de Angelman , Transtorno do Espectro Autista , Epigenômica , Deficiência Intelectual , Síndrome de Angelman/genética , Transtorno do Espectro Autista/genética , Criança , Humanos , Deficiência Intelectual/genética , Perda de Heterozigosidade
3.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052177

RESUMO

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (SHANK) gene-family were identified in patients with ASD, and Shank knock-out mouse models display autism-like phenotypes. SHANK3 proteins are not only expressed in the central nervous system (CNS). Here, we show expression in gastrointestinal (GI) epithelium and report a significantly different GI morphology in Shank3 knock-out (KO) mice. Further, we detected a significantly altered microbiota composition measured in feces of Shank3 KO mice that may contribute to inflammatory responses affecting brain development. In line with this, we found higher E. coli lipopolysaccharide levels in liver samples of Shank3 KO mice, and detected an increase in Interleukin-6 and activated astrocytes in Shank3 KO mice. We conclude that apart from its well-known role in the CNS, SHANK3 plays a specific role in the GI tract that may contribute to the ASD phenotype by extracerebral mechanisms.


Assuntos
Transtorno do Espectro Autista/microbiologia , Microbioma Gastrointestinal , Proteínas do Tecido Nervoso/genética , Animais , Astrócitos/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Lipopolissacarídeos/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
4.
Nat Genet ; 51(6): 973-980, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31133750

RESUMO

We address the challenge of detecting the contribution of noncoding mutations to disease with a deep-learning-based framework that predicts the specific regulatory effects and the deleterious impact of genetic variants. Applying this framework to 1,790 autism spectrum disorder (ASD) simplex families reveals a role in disease for noncoding mutations-ASD probands harbor both transcriptional- and post-transcriptional-regulation-disrupting de novo mutations of significantly higher functional impact than those in unaffected siblings. Further analysis suggests involvement of noncoding mutations in synaptic transmission and neuronal development and, taken together with previous studies, reveals a convergent genetic landscape of coding and noncoding mutations in ASD. We demonstrate that sequences carrying prioritized mutations identified in probands possess allele-specific regulatory activity, and we highlight a link between noncoding mutations and heterogeneity in the IQ of ASD probands. Our predictive genomics framework illuminates the role of noncoding mutations in ASD and prioritizes mutations with high impact for further study, and is broadly applicable to complex human diseases.


Assuntos
Transtorno do Espectro Autista/genética , Aprendizado Profundo , Predisposição Genética para Doença , Genoma Humano , Genômica , Mutação , RNA não Traduzido , Algoritmos , Alelos , Transtorno do Espectro Autista/diagnóstico , Biologia Computacional/métodos , Expressão Gênica , Regulação da Expressão Gênica , Genes Reporter , Estudos de Associação Genética , Genômica/métodos , Humanos , Fenótipo , Processamento Pós-Transcricional do RNA , Transcrição Genética
5.
Mol Autism ; 10: 15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962870

RESUMO

Background: Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. Methods: We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Results: Conventional heterozygous Scn2a knockout mice (Scn2a KO/+) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2a KO/+ mice with CX516. Additionally, Scn2a KO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2a KO/+ mice, with an increase in the gamma band. Conclusions: Scn2a KO/+ mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes.


Assuntos
Ansiedade/genética , Transtorno do Espectro Autista/genética , Memória , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Agitação Psicomotora/genética , Comportamento Social , Animais , Ansiedade/tratamento farmacológico , Transtorno do Espectro Autista/tratamento farmacológico , Dioxóis/uso terapêutico , Ritmo Gama , Haploinsuficiência , Masculino , Moduladores de Transporte de Membrana/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Piperidinas/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Agitação Psicomotora/tratamento farmacológico
6.
Biol Res Nurs ; 21(3): 335-342, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30983407

RESUMO

BACKGROUND: Sleep disturbance is a frequent comorbidity in children with autism spectrum disorder (ASD), affecting an estimated 40-80% of cases. Previous reports have shown relationships between several circadian rhythm-related genes and sleep problems in ASD. The purpose of the present study was to relate variation in and around melatonin synthesis and suprachiasmatic nucleus genes to sleep problems in a large sample of children with ASD. METHOD: This secondary analysis used existing genotypic and phenotypic data for 2,065 children, aged 4-18 years, from the Simons Simplex Collection (SSC). Sleep problems were measured with the SSC Sleep Interview. Expression quantitative trait loci and single nucleotide polymorphisms in 25 circadian genes were chosen primarily for their impact on expression levels of target genes in the brain. Associations between variants and composite sleep problems, nighttime problems, daytime problems, and sleep duration problems were calculated using logistic regression analysis. Age, sex, nonverbal IQ, ASD severity, gastrointestinal distress, seizures, and ancestry were included as covariates. Transmission disequilibrium tests were performed to test for overtransmission of alleles in the same variants. RESULTS: No significant associations or transmission disequilibrium were found between gene variants and sleep problems in this sample of children with ASD. CONCLUSION: Variation in expression of investigated genes in the melatonin synthesis and suprachiasmatic nucleus pathways did not have notable impacts on sleep problems in this large sample of children with ASD. Future research could explore translational and posttranslational effects of these genes or the effects of genes in other sleep-homeostasis pathways on sleep patterns.


Assuntos
Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Ritmo Circadiano/genética , Melatonina/biossíntese , Melatonina/genética , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Adolescente , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Masculino
7.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866437

RESUMO

Recent research revealed that autism spectrum disorders (ASD) and cancer may share common genetic architecture, with evidence first reported with the PTEN gene. There are approximately 800 autism genes and 3500 genes associated with cancer. The VarElect phenotype program was chosen to identify genes jointly associated with both conditions based on genomic information stored in GeneCards. In total, 138 overlapping genes were then profiled with GeneAnalytics, an analysis pathway enrichment tool utilizing existing gene datasets to identify shared pathways, mechanisms, and phenotypes. Profiling the shared gene data identified seven significantly associated diseases of 2310 matched disease entities with factors implicated in shared pathology of ASD and cancer. These included 371 super-pathways of 455 matched entities reflecting major cell-signaling pathways and metabolic disturbances (e.g., CREB, AKT, GPCR); 153 gene ontology (GO) biological processes of 226 matched processes; 41 GO molecular functions of 78 matched functions; and 145 phenotypes of 232 matched phenotypes. The entries were scored and ranked using a matching algorithm that takes into consideration genomic expression, sequencing, and microarray datasets with cell or tissue specificity. Shared mechanisms may lead to the identification of a common pathology and a better understanding of causation with potential treatment options to lessen the severity of ASD-related symptoms in those affected.


Assuntos
Transtorno do Espectro Autista/genética , Biologia Computacional/métodos , Redes Reguladoras de Genes , Neoplasias/genética , Algoritmos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Fenótipo
8.
Artigo em Inglês | MEDLINE | ID: mdl-30813406

RESUMO

One of the most common neurodevelopmental disorders worldwide is autism spectrum disorder (ASD), which is characterized by language delay, impaired communication interactions, and repetitive patterns of behavior caused by environmental and genetic factors. This review aims to provide a comprehensive survey of recently published literature on ASD and especially novel insights into excitatory synaptic transmission. Even though numerous genes have been discovered that play roles in ASD, a good understanding of the pathophysiologic process of ASD is still lacking. The protein⁻protein interactions between the products of NLGN, SHANK, and NRXN synaptic genes indicate that the dysfunction in synaptic plasticity could be one reason for the development of ASD. Designing more accurate diagnostic tests for the early diagnosis of ASD would improve treatment strategies and could enhance the appropriate monitoring of prognosis. This comprehensive review describes the psychotropic and antiepileptic drugs that are currently available as effective pharmacological treatments and provides in-depth knowledge on the concepts related to clinical, diagnostic, therapeutic, and genetic perspectives of ASD. An increase in the prevalence of ASD in Gulf Cooperation Council countries is also addressed in the review. Further, the review emphasizes the need for international networking and multidimensional studies to design novel and effective treatment strategies.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/tratamento farmacológico , Diagnóstico Precoce , Humanos , Oriente Médio/epidemiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêutico , Fatores de Risco , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética
9.
Atten Defic Hyperact Disord ; 11(1): 91-105, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30927234

RESUMO

Na+/H+ Exchanger 9 (NHE9) is an endosomal membrane protein encoded by the Solute Carrier 9A, member 9 gene (SLC9A9). SLC9A9 has been implicated in attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), epilepsy, multiple sclerosis and cancers. To better understand the function of NHE9 and the effects of disease-associated variants on protein-protein interactions, we conducted a quantitative analysis of the NHE9 interactome using co-immunoprecipitation and isobaric labeling-based quantitative mass spectrometry. We identified 100 proteins that interact with NHE9. These proteins were enriched in known functional pathways for NHE9: the endocytosis, protein ubiquitination and phagosome pathways, as well as some novel pathways including oxidative stress, mitochondrial dysfunction, mTOR signaling, cell death and RNA processing pathways. An ADHD-associated mutation (A409P) significantly altered NHE9's interactions with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling. An ASD nonsense mutation in SLC9A9, R423X, produced no-detectable amount of NHE9, suggesting the overall loss of NHE9 functional networks. In addition, seven of the NHE9 interactors are products of known autism candidate genes (Simons Foundation Autism Research Initiative, SFARI Gene) and 90% of the NHE9 interactome overlap with SFARI protein interaction network PIN (p < 0.0001), supporting the role of NHE9 interactome in ASDs molecular mechanisms. Our results provide a detailed understanding of the functions of protein NHE9 and its disrupted interactions, possibly underlying ADHD and ASDs. Furthermore, our methodological framework proved useful for functional characterization of disease-associated genetic variants and suggestion of druggable targets.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Mutação , Mapas de Interação de Proteínas/genética , Trocadores de Sódio-Hidrogênio/genética , Humanos
10.
Nat Neurosci ; 22(4): 556-564, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30911184

RESUMO

Heterozygous loss-of-function mutations in SHANK2 are associated with autism spectrum disorder (ASD). We generated cortical neurons from induced pluripotent stem cells derived from neurotypic and ASD-affected donors. We developed sparse coculture for connectivity assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed increases in dendrite length, dendrite complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 mutation. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in isogenic SHANK2 neurons was perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from ASD subjects.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Dendritos/patologia , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Transtorno do Espectro Autista/metabolismo , Técnicas de Cocultura , Dendritos/metabolismo , Potenciais Pós-Sinápticos Excitadores , Técnicas de Inativação de Genes , Haploinsuficiência , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Plasticidade Neuronal , Neurônios/metabolismo , Transcriptoma
11.
Mol Autism ; 10: 8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858964

RESUMO

Background: Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2α knockout (KO) model. Methods: Fixed brains of Nrxn2α KO mice underwent DTI using 9.4 T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. Results: DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2α KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Conclusions: Our findings demonstrate that deleting a single neurexin gene (Nrxn2α) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.


Assuntos
Transtorno do Espectro Autista/genética , Encéfalo/diagnóstico por imagem , Proteínas do Tecido Nervoso/genética , Animais , Transtorno do Espectro Autista/diagnóstico por imagem , Imagem de Tensor de Difusão , Deleção de Genes , Imagem Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Psychiatr Genet ; 29(3): 86-90, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30724859

RESUMO

About one child in 68 is affected by the autism spectrum disorder (ASD), one of the most common neurodevelopmental disorders linked to intellectual disability, especially in males, intellectual disability being diagnosable in about 60-70% of autistic individuals. The biological bases of ASD are not yet fully known, but they are generally considered multifactorial, although many genes and genomic loci have been proposed to be possibly associated with this condition. In this report, we describe the case of a 14-year-old female Italian proband affected by ASD, carrying a novel ~ 270 kb interstitial microduplication, localized at the distal portion of the 4q13.1 region. The rearrangement was inherited from a mild symptomatic father and included a large part of the single EPHA5 gene, a receptor tyrosine kinase involved in the neural development, already indicated to be linked to ASD by previous Genome Wide Association Studies. This imbalance represents, to the best of our knowledge, the smallest duplication identified to date that only impacts the EPHA5 gene. We hypothesize that the duplication of this gene may alter EPHA5 expression and that this may impact the autistic phenotype of the patient.


Assuntos
Transtorno do Espectro Autista/genética , Receptor EphA5/genética , Adolescente , Transtorno Autístico/genética , Hibridização Genômica Comparativa , Feminino , Duplicação Gênica/genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Deficiência Intelectual/genética , Itália , Fenótipo , Receptor EphA5/fisiologia
13.
J Pharmacol Sci ; 139(3): 249-253, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30718079

RESUMO

The duplication of human chromosome 15q11-13 is known to be associated with an estimated 1.1% of autism cases. Here, we investigated whether differentiation into neurons and astrocytes is altered in fetal neural stem cells (FNSCs) isolated from the mouse model of 15q11-13 duplication syndrome (patDp/+ mice). In patDp/+ mice-derived FNSCs, multipotency was maintained for a longer period, the population of neurons was downregulated, and that of astrocytes was upregulated significantly after differentiation induction. These results suggest that the dysregulation of FNSCs differentiation could affect cortical development and behavioral deficits in the early postnatal stage shown in the patDp/+ mice.


Assuntos
Transtorno do Espectro Autista/genética , Diferenciação Celular/fisiologia , Deficiência Intelectual/fisiopatologia , Células-Tronco Neurais/citologia , Animais , Astrócitos/citologia , Transtorno do Espectro Autista/fisiopatologia , Aberrações Cromossômicas , Cromossomos Humanos Par 15 , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia
14.
Transl Psychiatry ; 9(1): 50, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705255

RESUMO

The molecular signature underlying autism spectrum disorder remains largely unknown. This study identifies differential expression of mTOR and MAPK pathways in patients affected by mild and severe idiopathic autism. A total of 55 subjects were enrolled, of which 22 were typically developing individuals and 33 were patients aged between 3 and 11 years, with autism spectrum disorder. A detailed history, including physical examination, developmental evaluation, mental health history and autism diagnostic observation schedule were performed for each patient. Components of the mTOR and MAPK signalling pathways were analysed from peripheral blood at the protein level. Patients were then stratified according to their clinical phenotypes, and the molecular profiling was analysed in relation to the degree of autism severity. In this cohort of patients, we identified increased activity of mTOR and the MAPK pathways, key regulators of synaptogenesis and protein synthesis. Specifically, rpS6, p-eIF4E, TSC1 and p-MNK1 expression discriminated patients according to their clinical diagnosis, suggesting that components of protein synthesis signalling pathways might constitute a molecular signature of clinical severity in autism spectrum disorder.


Assuntos
Transtorno do Espectro Autista/genética , Sistema de Sinalização das MAP Quinases/genética , Neurogênese/genética , Serina-Treonina Quinases TOR/genética , Criança , Pré-Escolar , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética
15.
Mol Imaging ; 18: 1536012118821034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799683

RESUMO

MET, the gene encoding the tyrosine kinase receptor for hepatocyte growth factor, is a susceptibility gene for autism spectrum disorder (ASD). Genetically altered mice with a kinase-inactive Met offer a potential model for understanding neural circuit organization changes in autism. Here, we focus on the somatosensory thalamocortical circuitry because distinct somatosensory sensitivity phenotypes accompany ASD, and this system plays a major role in sensorimotor and social behaviors in mice. We employed resting-state functional magnetic resonance imaging and in vivo high-resolution proton MR spectroscopy to examine neuronal connectivity and neurotransmission of wild-type, heterozygous Met-Emx1, and fully inactive homozygous Met-Emx1 mice. Met-Emx1 brains showed impaired maturation of large-scale somatosensory network connectivity when compared with wild-type controls. Significant sex × genotype interaction in both network features and glutamate/gamma-aminobutyric acid (GABA) balance was observed. Female Met-Emx1 brains showed significant connectivity and glutamate/GABA balance changes in the somatosensory thalamocortical system when compared with wild-type brains. The glutamate/GABA ratio in the thalamus was correlated with the connectivity between the somatosensory cortex and the thalamus in heterozygous Met-Emx1 female brains. The findings support the hypothesis that aberrant functioning of the somatosensory thalamocortical system is at the core of the conspicuous somatosensory behavioral phenotypes observed in Met-Emx1 mice.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Proteínas Proto-Oncogênicas c-met/genética , Córtex Somatossensorial/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Mapeamento Encefálico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Somatossensorial/metabolismo , Tálamo/metabolismo , Ácido gama-Aminobutírico/metabolismo
16.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
17.
Proc Natl Acad Sci U S A ; 116(9): 3853-3862, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30755521

RESUMO

The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT have been associated with DA dysfunction, a complication associated with several brain disorders, including autism spectrum disorder (ASD). Here, we investigated the structural and behavioral bases of an ASD-associated in-frame deletion in hDAT at N336 (∆N336). We uncovered that the deletion promoted a previously unobserved conformation of the intracellular gate of the transporter, likely representing the rate-limiting step of the transport process. It is defined by a "half-open and inward-facing" state (HOIF) of the intracellular gate that is stabilized by a network of interactions conserved phylogenetically, as we demonstrated in hDAT by Rosetta molecular modeling and fine-grained simulations, as well as in its bacterial homolog leucine transporter by electron paramagnetic resonance analysis and X-ray crystallography. The stabilization of the HOIF state is associated both with DA dysfunctions demonstrated in isolated brains of Drosophila melanogaster expressing hDAT ∆N336 and with abnormal behaviors observed at high-time resolution. These flies display increased fear, impaired social interactions, and locomotion traits we associate with DA dysfunction and the HOIF state. Together, our results describe how a genetic variation causes DA dysfunction and abnormal behaviors by stabilizing a HOIF state of the transporter.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Dopamina/genética , Locomoção/genética , Animais , Animais Geneticamente Modificados , Transtorno do Espectro Autista/fisiopatologia , Cristalografia por Raios X , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Espectroscopia de Ressonância de Spin Eletrônica , Medo/fisiologia , Humanos , Relações Interpessoais , Locomoção/fisiologia , Modelos Moleculares , Mutação , Deleção de Sequência/genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-30797015

RESUMO

In recent years, there has been an explosive increase in genetic studies related to autism spectrum disorder (ASD). This implicated the accumulation of a large amount of molecular data that may be used to verify various hypotheses and models developed to explore the complex genetic component of ASD. Several lines of evidence support the view that structural genomic variation contributes to the pathogenesis of ASD. The introduction of more sophisticated techniques for whole-genome screening, including array comparative genome hybridization and high-resolution single nucleotide polymorphism analysis, has allowed to identify an increasing number of ASD susceptibility loci. Copy number variants (CNVs) are the most common type of structural variation in the human genome and are considered important contributors to the pathogenesis of neurodevelopmental disorders, including ASD. In this review, we describe the accumulated evidence concerning the genetic events associated with ASD, and summarize current knowledge about the clinical relevance of CNVs in these disorders.


Assuntos
Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Humanos
19.
Mol Autism ; 10: 5, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30792833

RESUMO

Background: Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by Tbr1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in Tbr1 mutant mice. Methods: We used Tbr1 +/- mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of Tbr1 +/- mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Results: Tbr1 +/- mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. Tbr1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of Tbr1 +/- olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by Tbr1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in Tbr1 +/- mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in Tbr1 +/- mice, suggesting that increased neuronal activity has a beneficial effect on Tbr1 deficiency. Conclusions: Tbr1 regulates neural circuits and activity in the olfactory system to control olfaction. Tbr1 +/- mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Ligação a DNA/genética , Discriminação (Psicologia) , Haploinsuficiência , Percepção Olfatória , Animais , Ciclosserina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/patologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/patologia , Bulbo Olfatório/fisiologia , Receptores de N-Metil-D-Aspartato/agonistas , Olfato
20.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA