Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.317
Filtrar
1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 935-937, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515794

RESUMO

OBJECTIVE: To explore the genetic basis for a patient with autism. METHODS: High-throughput sequencing was carried out to detect copy number variations in the patient. RESULTS: DNA sequencing found that the patient has carried a 0.11 Mb deletion in distal 2p16.3 spanning from genomic position 50 820 001 to 50 922 000, which resulted removal of exon 6 and part of intron 7 of the NRXN1 gene. The same deletion was not found his parents and brother. CONCLUSION: Partial deletion of the NRXN1 gene may underlie the disease in this patient.


Assuntos
Transtorno Autístico/genética , Moléculas de Adesão Celular Neuronais/genética , Deleção de Genes , Proteínas do Tecido Nervoso/genética , Variações do Número de Cópias de DNA , Humanos , Masculino
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 829-833, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400139

RESUMO

OBJECTIVE: To explore the genetic basis for a family affected with mental retardation combined with autism. METHODS: For the family featuring X-linked recessive inheritance of mental retardation combined with autism, clinical data and peripheral blood samples were collected. Potential mutations of genes associated with intellectual impairment were sequenced with an Ion PGM platform. Suspected mutations were verified with a PCR-Sanger sequencing method. RESULTS: The patient with mental retardation had mild abnormal electroencephalograph(EEG), while brain MRI and CT scans showed no obvious abnormality. Two ABC (autism behavior checklist) testing scores were 73 and 66 when he was 7- and 13-year-old, respectively. A novel hemizygous mutation, c.64C>T (p.L22F), was detected in the GRIA3 gene in the patient, for which his mother was a heterozygous carrier. The mutation site was predicted to be possibly damaging and disease causing by PolyPhen_2 and MutationTaster. CONCLUSION: The novel hemizygous c.64C>T (p.L22F) mutation of the GRIA3 gene probably underlies the phenotypes of mental retardation combined with autism in this family. Considering the variable clinical manifestation of mental retardation and genetic heterogeneity of autism, genetic testing is essential for making the correct diagnosis.


Assuntos
Transtorno Autístico/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Receptores de AMPA/genética , Adolescente , Criança , Humanos , Masculino , Mutação
3.
Neuron ; 103(4): 617-626.e6, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31257103

RESUMO

The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.


Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Transtorno Autístico/genética , Moléculas de Adesão Celular Neuronais/genética , Células Cultivadas , Córtex Cerebral/fisiologia , Células-Tronco Embrionárias/citologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Genes Reporter , Ácido Glutâmico/fisiologia , Humanos , Camundongos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Mutação de Sentido Incorreto , Neurogênese , Neurônios/fisiologia , Fenótipo , Receptores de Glutamato/fisiologia , Especificidade da Espécie , Sinapses/química
4.
BMC Bioinformatics ; 20(Suppl 12): 313, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31216978

RESUMO

BACKGROUND: Schizophrenia and autism are examples of polygenic diseases caused by a multitude of genetic variants, many of which are still poorly understood. Recently, both diseases have been associated with disrupted neuron motility and migration patterns, suggesting that aberrant cell motility is a phenotype for these neurological diseases. RESULTS: We formulate the POLYGENIC DISEASE PHENOTYPE Problem which seeks to identify candidate disease genes that may be associated with a phenotype such as cell motility. We present a machine learning approach to solve this problem for schizophrenia and autism genes within a brain-specific functional interaction network. Our method outperforms peer semi-supervised learning approaches, achieving better cross-validation accuracy across different sets of gold-standard positives. We identify top candidates for both schizophrenia and autism, and select six genes labeled as schizophrenia positives that are predicted to be associated with cell motility for follow-up experiments. CONCLUSIONS: Candidate genes predicted by our method suggest testable hypotheses about these genes’ role in cell motility regulation, offering a framework for generating predictions for experimental validation.


Assuntos
Movimento Celular/genética , Doença/genética , Redes Reguladoras de Genes , Herança Multifatorial/genética , Algoritmos , Transtorno Autístico/genética , Estudos de Associação Genética , Humanos , Aprendizado de Máquina , Fenótipo , Curva ROC , Reprodutibilidade dos Testes , Esquizofrenia/genética
5.
Gene ; 706: 162-171, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31085274

RESUMO

In clinical genetics, the need to discriminate between benign and pathogenic variants identified in patients with neurodevelopmental disorders is an absolute necessity. Copy number variants (CNVs) of small size can enable the identification of genes that are critical for neurologic development. However, assigning a definite association with a specific disorder is a difficult task. Among 328 trios analyzed over seven years of activity in a single laboratory, we identified 19 unrelated patients (5.8%) who carried a small (<500 kb) de novo CNV. Four patients had an additional independent de novo CNV. Nine had a variant that could be assigned as definitely pathogenic, whereas the remaining CNVs were considered as variants of unknown significance (VUS). We report clinical and molecular findings of patients harboring VUS. We reviewed the medical literature available for genes impacted by CNVs, obtained the probability of truncating loss-of-function intolerance, and compared overlapping CNVs reported in databases. The classification of small non-recurrent CNVs remains difficult but, among our findings, we provide support for a role of SND1 in the susceptibility of autism, describe a new case of the rare 17p13.1 microduplication syndrome, and report an X-linked duplication involving KIF4A and DLG3 as a likely cause of epilepsy.


Assuntos
Variações do Número de Cópias de DNA/genética , Transtornos do Neurodesenvolvimento/genética , Adulto , Transtorno Autístico/genética , Criança , Pré-Escolar , Epilepsia/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Cinesina/genética , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Fatores de Transcrição/genética
6.
Eur J Med Genet ; 62(7): 103648, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30998997

RESUMO

CANAC1C encodes for the main cardiac L-type calcium channel and mutations on it lead to a prolonged QT interval in Timothy Syndrome (TS). We provide a new de novo constitutional heterozygote missense variation in CACNA1C in a living adult woman, also carrier of the known c.2146-1G>C heterozygous variation of PKP2 inherited from her father. To our knowledge, this patient is the first to have the two variations in these genes. Theses clinical and molecular findings expand the clinical and molecular spectrum of TS and show the interest of next generation sequencing or whole exome sequencing in rare disorders, atypical or novel phenotype.


Assuntos
Transtorno Autístico/genética , Canais de Cálcio Tipo L/genética , Síndrome do QT Longo/genética , Fenótipo , Sindactilia/genética , Adulto , Transtorno Autístico/patologia , Feminino , Heterozigoto , Humanos , Síndrome do QT Longo/patologia , Mutação , Placofilinas/genética , Sindactilia/patologia
7.
Mol Autism ; 10: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31007884

RESUMO

Background: Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Methods: Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis and report gene, pathway, and drug set-based overlaps between them. Results: Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. Conclusions: Comparisons of ASD and cancer differential gene expression meta-analysis results suggest that brain, kidney, thyroid, and pancreatic cancers are candidates for direct comorbid associations with ASD. On the other hand, lung and prostate cancers are candidates for inverse comorbid associations with ASD. Joint perturbations in a set of specific biological processes underlie these associations which include several pathways previously implicated in both cancer and ASD encompassing immune system alterations, impairments of energy metabolism, cell cycle, and signaling through PI3K and G protein-coupled receptors among others. These findings could help to explain epidemiological observations pointing towards direct and inverse comorbid associations between ASD and specific cancer types and depict a complex scenario regarding the molecular patterns of association between ASD and cancer.


Assuntos
Transtorno Autístico/genética , Encéfalo/metabolismo , Neoplasias/genética , Transcriptoma , Transtorno Autístico/epidemiologia , Humanos , Neoplasias/epidemiologia , Transdução de Sinais/genética
8.
Artigo em Inglês | MEDLINE | ID: mdl-30853900

RESUMO

Research efforts over the past decades have unraveled both genetic and environmental factors, which contribute to the development of autism spectrum disorders (ASD). It is, to date, largely unknown how different underlying causes result in a common phenotype. However, the individual course of development and the different comorbidities might reflect the heterogeneous genetic and non-genetic contributions. Therefore, it is reasonable to identify commonalities and differences in models of these disorders at the different hierarchical levels of brain function, including genetics/environment, cellular/synaptic functions, brain regions, connectivity, and behavior. To that end, we investigated Shank3 transgenic mouse lines and compared them with a prenatal zinc-deficient (PZD) mouse model of ASD at the level of brain structural alterations in an 11,7 T small animal magnetic resonance imaging (MRI). Animals were measured at 4 and 9 weeks of age. We identified a decreased total brain volume (TBV) and hippocampal size of Shank3 -/- mice but a convergent increase of basal ganglia (striatum and globus pallidus) in most mouse lines. Moreover, Shank3 transgenic mice had smaller thalami, whereas PZD mice had this region enlarged. Intriguingly, Shank3 heterozygous knockout mice mostly showed minor abnormalities to full knockouts, which might reflect the importance of proper Shank3 dosage in neuronal cells. Most reported volume changes seemed to be more pronounced at younger age. Our results indicate both convergent and divergent brain region abnormalities in genetic and non-genetic models of ASD. These alterations of brain structures might be mirrored in the reported behavior of both models, which have not been assessed in this study.


Assuntos
Transtorno Autístico , Encéfalo/diagnóstico por imagem , Desnutrição/complicações , Proteínas do Tecido Nervoso/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Zinco/deficiência , Fatores Etários , Animais , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/genética , Transtorno Autístico/patologia , Modelos Animais de Doenças , Feminino , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Gravidez
9.
Mol Autism ; 10: 12, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918622

RESUMO

Background: Autism is a highly varied and heritable neurodevelopmental condition, and common variants explain approximately 50% of the genetic variance of autism. One of the genes implicated in autism is the oxytocin receptor (OXTR). The current study combined genetic and brain imaging (fMRI) data to examine the moderating effect of genotype on the association between diagnosis and brain activity in response to a test of cognitive empathy. Methods: Participants were adolescents (mean age = 14.7 ± 1.7) who were genotyped for single nucleotide polymorphisms (SNPs) within the OXTR and underwent functional brain imaging while completing the adolescent version of the 'Reading the Mind in the Eyes' Test (Eyes Test). Results: Two (rs2254298, rs53576) of the five OXTR SNPs examined were significantly associated with brain activity during the Eyes Test, and three of the SNPs (rs2254298, rs53576, rs2268491) interacted with diagnostic status to predict brain activity. All of the effects localized to the right supramarginal gyrus (rSMG) and an overlap analysis revealed a large overlap of the effects. An exploratory analysis showed that activity within an anatomically defined rSMG and genotype can predict diagnostic status with reasonable accuracy. Conclusions: This is one of the first studies to investigate OXTR and brain function in autism. The findings suggest a neurogenetic mechanism by which OXTR-dependent activity within the rSMG is related to the aetiology of autism.


Assuntos
Transtorno Autístico/genética , Reconhecimento Facial , Polimorfismo de Nucleotídeo Único , Receptores de Ocitocina/genética , Adolescente , Transtorno Autístico/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Criança , Emoções , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino
10.
Mol Autism ; 10: 11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911366

RESUMO

Autism (MIM 209850) is a multifactorial disorder with a broad clinical presentation. A number of high-confidence ASD risk genes are known; however, the contribution of non-genetic environmental factors towards ASD remains largely uncertain. Here, we present a bioinformatics resource of genetic and induced models of ASD developed using a shared annotation platform. Using this data, we depict the intricate trends in the research approaches to analyze rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from rodent models of ASD based on 787 publications. As expected, many of these include animal model equivalents of the "core" phenotypes associated with ASD, such as impairments in social behavior and repetitive behavior, as well as several comorbid features of ASD including anxiety, seizures, and motor-control deficits. These phenotypes have also been studied in models based on a broad range of environmental inducers present in the database, of which gestational exposure to valproic acid (VPA) and maternal immune activation models comprising lipopolysaccharide (LPS) and poly I:C are the most studied. In our unique dataset of rescue models, we identify 24 pharmaceutical agents tested on established models derived from various ASD genes and CNV loci for their efficacy in mitigating symptoms relevant for ASD. As a case study, we analyze a large collection of Shank3 mouse models providing a high-resolution view of the in vivo role of this high-confidence ASD gene, which is the gateway towards understanding and dissecting the heterogeneous phenotypes seen in single-gene models of ASD. The trends described in this study could be useful for researchers to compare ASD models and to establish a complete profile for all relevant animal models in ASD research.


Assuntos
Transtorno Autístico/genética , Modelos Animais de Doenças , Fenótipo , Animais , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/patologia , Bases de Dados Genéticas , Camundongos , Ratos , Pesquisa Médica Translacional/normas
11.
Nat Commun ; 10(1): 1431, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926797

RESUMO

Autism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development. Here, we investigate the physiological role of Gprasp2, a gene linked to neurodevelopmental disabilities and involved in the postendocytic sorting of G-protein-coupled receptors. We show that Gprasp2 deletion leads to ASD-like behaviour in mice and alterations in synaptic communication. Manipulating the levels of Gprasp2 bidirectionally modulates the surface availability of mGluR5 and produces alterations in dendritic complexity, spine density and synaptic maturation. Loss of Gprasp2 leads to enhanced hippocampal long-term depression, consistent with facilitated mGluR-dependent activation. These findings demonstrate a role for Gprasp2 in glutamatergic synapses and suggest a possible mechanism by which this gene is linked to neurodevelopmental diseases.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/psicologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Plasticidade Neuronal/genética , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Comportamento Animal , Espinhas Dendríticas/patologia , Espinhas Dendríticas/ultraestrutura , Deleção de Genes , Hipocampo/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Memória , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Transmissão Sináptica
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(2): 157-160, 2019 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-30703237

RESUMO

OBJECTIVE: To carry out genome-wide copy number variations (CNVs) analysis for a boy with autism by using single nucleotide polymorphism array (SNP array). METHODS: SNP array analysis was conducted for the boy and his parents, and the data was validated by real-time PCR. Correlation between the deleted genes and the phenotype was analyzed by reviewing the literature. RESULTS: The patient was found to carry a terminal deletion of 18q22.3q23 (7.1 Mb), which involved FBXO15, ZNF407, ZADH2, TSHZ1, MBP and ADNP2 genes. No pathogenic CNVs were found in the parents. Comparison of the patient with cases reported in the literature suggested that the ZNF407 gene probably accounts for the autistic phenotype in these patients. CONCLUSION: The autistic phenotype of the patient may be attributed to the 18q deletion, for which ZNF407 may be a critical candidate. SNP array has provided an useful tool for the study of molecular mechanism underlying autism.


Assuntos
Transtorno Autístico , Variações do Número de Cópias de DNA , Transtorno Autístico/genética , Humanos , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único
15.
Mol Autism ; 10: 3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30733854

RESUMO

Background and aims: Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods: To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abΔC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abΔC +/- heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results: Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abΔC +/- mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abΔC +/- mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abΔC +/- and shank3abΔC -/- mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abΔC +/- larvae. Conclusions: Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD.


Assuntos
Transtorno Autístico/genética , Motilidade Gastrointestinal , Proteínas do Tecido Nervoso/genética , Proteínas de Peixe-Zebra/genética , Animais , Transtorno Autístico/fisiopatologia , Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/metabolismo , Células Enteroendócrinas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/citologia , Intestinos/crescimento & desenvolvimento , Intestinos/fisiologia , Mutação , Neurônios/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Serotonina/metabolismo , Peixe-Zebra
16.
BMC Bioinformatics ; 20(1): 92, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808299

RESUMO

BACKGROUND: Accurate identification of perturbed signaling pathways based on differentially expressed genes between sample groups is one of the key factors in the understanding of diseases and druggable targets. Most pathway analysis methods prioritize impacted signaling pathways by incorporating pathway topology using simple graph-based models. Despite their relative success, these models are limited in describing all types of dependencies and interactions that exist in biological pathways. RESULTS: In this work, we propose a new approach based on the formal modeling of signaling pathways. Signaling pathways are formally modeled, and then model checking tools are applied to find the likelihood of perturbation for each pathway in a given condition. By adopting formal methods, various complex interactions among biological parts are modeled, which can contribute to reducing the false-positive rate of the proposed approach. We have developed a tool named Formal model checking based pathway analysis (FoPA) based on this approach. FoPA is compared with three well-known pathway analysis methods: PADOG, CePa, and SPIA on the benchmark of 36 GEO datasets from various diseases by applying the target pathway technique. This validation technique eliminates the need for possibly biased human assessments of results. In the cases that, there is no apriori knowledge of all relevant pathways, simulated false inputs (permuted class labels and decoy pathways) are chosen as a set of negative controls to test the false positive rate of the methods. Finally, to further evaluate the efficiency of FoPA, it is applied to a list of autism-related genes. CONCLUSIONS: The results obtained by the target pathway technique demonstrate that FoPA is able to prioritize target pathways as well as PADOG but better than CePa and SPIA. Also, the false-positive rate of finding significant pathways using FoPA is lower than other compared methods. Also, FoPA can detect more consistent relevant pathways than other methods. The results of FoPA on autism-related genes highlight the role of "Renin-angiotensin system" pathway. This pathway has been supposed to have a pivotal role in some neurodegenerative diseases, while little attention has been paid to its impact on autism development so far.


Assuntos
Transdução de Sinais , Software , Transtorno Autístico/genética , Viés , Neoplasias Colorretais/metabolismo , Bases de Dados como Assunto , Reações Falso-Positivas , Humanos , Modelos Teóricos , Transdução de Sinais/genética
17.
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
19.
Neuron ; 101(4): 648-661.e4, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30679017

RESUMO

Distinct genetic forms of autism are hypothesized to share a common increase in excitation-inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide a systematic test of this hypothesis across 4 mouse models (Fmr1-/y, Cntnap2-/-, 16p11.2del/+, Tsc2+/-), focusing on somatosensory cortex. All autism mutants showed reduced feedforward inhibition in layer 2/3 coupled with more modest, variable reduction in feedforward excitation, driving a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization, and spontaneous spiking were largely normal. Modeling revealed that E and I conductance changes in each mutant were quantitatively matched to yield stable, not increased, synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo despite detectably reduced inhibition. Thus, elevated E-I ratio is a common circuit phenotype but appears to reflect homeostatic stabilization of synaptic drive rather than driving network hyperexcitability in autism.


Assuntos
Transtorno Autístico/fisiopatologia , Potenciais Somatossensoriais Evocados , Potenciais Pós-Sinápticos Excitadores , Potenciais Pós-Sinápticos Inibidores , Córtex Somatossensorial/fisiopatologia , Animais , Transtorno Autístico/genética , Cromossomos Humanos Par 16/genética , Proteína do X Frágil de Retardo Mental/genética , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Córtex Somatossensorial/fisiologia , Proteína 2 do Complexo Esclerose Tuberosa/genética
20.
Proc Natl Acad Sci U S A ; 116(6): 2175-2180, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30659153

RESUMO

The potential impact of structural variants includes not only the duplication or deletion of coding sequences, but also the perturbation of noncoding DNA regulatory elements and structural chromatin features, including topological domains (TADs). Structural variants disrupting TAD boundaries have been implicated both in cancer and developmental disease; this likely occurs via "enhancer hijacking," whereby removal of the TAD boundary exposes enhancers to new target transcription start sites (TSSs). With this functional role, we hypothesized that boundaries would display evidence for negative selection. Here we demonstrate that the chromatin landscape constrains structural variation both within healthy humans and across primate evolution. In contrast, in patients with developmental delay, variants occur remarkably uniformly across genomic features, suggesting a potentially broad role for enhancer hijacking in human disease.


Assuntos
Cromatina/química , Cromatina/genética , Evolução Molecular , Variação Genética , Animais , Transtorno Autístico/genética , Cromatina/metabolismo , Deficiências do Desenvolvimento/genética , Duplicação Gênica , Genoma , Genômica/métodos , Hominidae/genética , Humanos , Deleção de Sequência , Sítio de Iniciação de Transcrição
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA