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1.
Curr Opin Neurobiol ; 59: 102-111, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31220745

RESUMO

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by social deficits and restrictive and/or repetitive behaviors. The breadth of ASD symptoms is paralleled by the multiplicity of genes that have been implicated in its etiology. Initial findings revealed numerous ASD risk genes that contribute to synaptic function. More recently, genomic and gene expression studies point to altered chromatin function and impaired transcriptional control as additional risk factors for ASD. The consequences of impaired transcriptional alterations in ASD involve consistent changes in synaptic gene expression and cortical neuron specification during brain development. The multiplicity of genetic and environmental factors associated with ASD risk and their convergence onto common molecular pathways in neurons point to ASD as a disorder of gene regulatory networks.

2.
Nat Genet ; 51(7): 1092-1098, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31209396

RESUMO

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2-4 and rare de novo variants5-10 in ASD. Recessive mutations have also been implicated11-14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.

3.
Cereb Cortex ; 29(5): 2228-2244, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877790

RESUMO

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. It is a leading monogenic cause of autism spectrum disorder and inherited intellectual disability and is often comorbid with attention deficits. Most FXS cases are due to an expansion of CGG repeats leading to suppressed expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA metabolism. We found that the previously published Fmr1 knockout rat model of FXS expresses an Fmr1 transcript with an in-frame deletion of exon 8, which encodes for the K-homology (KH) RNA-binding domain, KH1. Notably, 3 pathogenic missense mutations associated with FXS lie in the KH domains. We observed that the deletion of exon 8 in rats leads to attention deficits and to alterations in transcriptional profiles within the medial prefrontal cortex (mPFC), which map to 2 weighted gene coexpression network modules. These modules are conserved in human frontal cortex and enriched for known FMRP targets. Hub genes in these modules represent potential therapeutic targets for FXS. Taken together, these findings indicate that attentional testing might be a reliable cross-species tool for investigating FXS and identify dysregulated conserved gene networks in a relevant brain region.

4.
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
6.
Cell Rep ; 24(13): 3441-3454.e12, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257206

RESUMO

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

7.
Nat Commun ; 9(1): 2064, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802345

RESUMO

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.

8.
Mol Autism ; 9: 31, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719671

RESUMO

Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3.


Assuntos
Transtornos Cromossômicos/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Mutação Puntual , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Feminino , Haploinsuficiência , Humanos , Masculino
9.
Curr Opin Neurobiol ; 48: 106-112, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29222989

RESUMO

Autism spectrum disorder (ASD) and intellectual disability (ID) are caused by a wide range of genetic mutations, a significant fraction of which reside in genes important for synaptic function. Studies have found that sensory, prefrontal, hippocampal, cerebellar, and striatal regions, as well as the circuits that connect them, are perturbed in mouse models of ASD and ID. Dissecting the disruptions in morphology and activity in these neural circuits might help us to understand the shared risk between the two disorders as well as their clinical heterogeneity. Treatments that target the balance between excitation and inhibition in these regions are able to reverse pathological phenotypes, elucidating this deficit as a commonality across models and opening new avenues for intervention.

10.
Mol Autism ; 8: 57, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29090079

RESUMO

BACKGROUND: Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. METHODS: Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5-17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. RESULTS: We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. CONCLUSIONS: This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.


Assuntos
Transtorno do Espectro Autista/genética , Fatores de Transcrição Forkhead/genética , Proteínas Repressoras/genética , Adolescente , Sequência de Aminoácidos , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , DNA/química , DNA/metabolismo , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico , Feminino , Testes Genéticos , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Transtornos da Linguagem/complicações , Transtornos da Linguagem/diagnóstico , Masculino , Mutação de Sentido Incorreto , Fenótipo , Polimorfismo Genético , Estudos Prospectivos , Ligação Proteica , Estrutura Terciária de Proteína
11.
Front Mol Neurosci ; 10: 212, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28713243

RESUMO

Altered synaptic function has been associated with neurological and psychiatric conditions including intellectual disability, schizophrenia and autism spectrum disorder (ASD). Amongst the recently discovered synaptic proteins is p140Cap, an adaptor that localizes at dendritic spines and regulates their maturation and physiology. We recently showed that p140Cap knockout mice have cognitive deficits, impaired long-term potentiation (LTP) and long-term depression (LTD), and immature, filopodia-like dendritic spines. Only a few p140Cap interacting proteins have been identified in the brain and the molecular complexes and pathways underlying p140Cap synaptic function are largely unknown. Here, we isolated and characterized the p140Cap synaptic interactome by co-immunoprecipitation from crude mouse synaptosomes, followed by mass spectrometry-based proteomics. We identified 351 p140Cap interactors and found that they cluster to sub complexes mostly located in the postsynaptic density (PSD). p140Cap interactors converge on key synaptic processes, including transmission across chemical synapses, actin cytoskeleton remodeling and cell-cell junction organization. Gene co-expression data further support convergent functions: the p140Cap interactors are tightly co-expressed with each other and with p140Cap. Importantly, the p140Cap interactome and its co-expression network show strong enrichment in genes associated with schizophrenia, autism, bipolar disorder, intellectual disability and epilepsy, supporting synaptic dysfunction as a shared biological feature in brain diseases. Overall, our data provide novel insights into the molecular organization of the synapse and indicate that p140Cap acts as a hub for postsynaptic complexes relevant to psychiatric and neurological disorders.

12.
Nat Neurosci ; 20(9): 1217-1224, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28714951

RESUMO

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.


Assuntos
Transtorno do Espectro Autista/genética , Bases de Dados Genéticas/tendências , Variação Genética/genética , Mutação de Sentido Incorreto/genética , Predisposição Genética para Doença/genética , Humanos , Mosaicismo , Zigoto/fisiologia
13.
Acta Neuropathol ; 134(4): 537-566, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28584888

RESUMO

Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.


Assuntos
Transtorno do Espectro Autista/patologia , Encéfalo/patologia , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Neurônios/metabolismo , Neurônios/patologia
14.
Am J Med Genet B Neuropsychiatr Genet ; 171B(2): 290-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26620927

RESUMO

Copy number variation (CNV) has been associated with a variety of neuropsychiatric disorders, including intellectual disability/developmental delay (ID/DD), autism spectrum disorder (ASD), and schizophrenia (SCZ). Often, individuals carrying the same pathogenic CNV display high clinical variability. By array-CGH analysis, we identified a novel familial 3q29 deletion (1.36 Mb), centromeric to the 3q29 deletion region, which manifests with variable expressivity. The deletion was identified in a 3-year-old girl diagnosed with ID/DD and autism and segregated in six family members, all affected by severe psychiatric disorders including schizophrenia, major depression, anxiety disorder, and personality disorder. All individuals carrying the deletion were overweight or obese, and anomalies compatible with optic atrophy were observed in three out of four cases examined. Amongst the 10 genes encompassed by the deletion, the haploinsufficiency of Optic Atrophy 1 (OPA1), associated with autosomal dominant optic atrophy, is likely responsible for the ophthalmological anomalies. We hypothesize that the haploinsufficiency of ATPase type 13A4 (ATP13A4) and/or Hairy/Enhancer of Split Drosophila homolog 1 (HES1) contribute to the neuropsychiatric phenotype, while HES1 deletion might underlie the overweight/obesity. In conclusion, we propose a novel contiguous gene syndrome due to a proximal 3q29 deletion variably associated with autism, ID/DD, psychiatric traits and overweight/obesity.


Assuntos
Transtorno Autístico/genética , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Deficiência Intelectual/genética , Obesidade/genética , Transtornos Psicóticos/genética , Adulto , Idoso , Transtorno Autístico/complicações , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/complicações , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Transtornos Psicóticos/complicações
15.
J Chem Theory Comput ; 11(7): 3401-10, 2015 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-26575774

RESUMO

Cytoplasmic FMRP interacting protein 1 (CYFIP1), also known as specifically RAC1 activated protein 1 (Sra1), plays a dual role: together with fragile X mental retardation protein (FMRP) and eIF4E it forms a complex that inhibits mRNA translation, while together with WAVE1, NCKAP1, ABI2, and HSPC300 it forms the WAVE regulatory complex (WRC) that upon RAC1 activation initiates actin polymerization. Here we performed a molecular dynamics (MD) simulation on CYFIP1 extracted from the known WRC structure, which shows that, in the absence of its WRC partners, a butterfly-like motion brings the two ends of CYFIP1 closer together, enabling the interaction with eIF4E. Our MD simulation is supported by available data showing that binding of CYFIP1 to eIF4E and binding to the WRC are mutually exclusive and that there is fluorescence resonance energy transfer between the N- and C-termini of CYFIP1. The differential interaction of RAC1-GTP with the two CYFIP1 structures predicts that RAC1 is directly responsible for the switch between these conformations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Movimento , Humanos
16.
J Child Neurol ; 30(14): 1861-70, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26350728

RESUMO

Phelan-McDermid syndrome or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder characterized by generalized developmental delay, intellectual disability, absent or delayed speech, seizures, autism spectrum disorder, neonatal hypotonia, physical dysmorphic features, and recurrent medical comorbidities. Individuals with Phelan-McDermid syndrome have terminal deletions of the chromosomal region 22q13.3 encompassing SHANK3, a gene encoding a structural component of excitatory synapses indispensable for proper synaptogenesis and neuronal physiology, or point mutations within the gene. Here, we review the clinical aspects of the syndrome and the genetic findings shedding light onto the underlying etiology. We also provide an overview on the evidence from genetic studies and mouse models that supports SHANK3 haploinsufficiency as a major contributor of the neurobehavioral manifestations of Phelan-McDermid syndrome. Finally, we discuss how all these discoveries are uncovering the pathophysiology of Phelan-McDermid syndrome and are being translated into clinical trials for novel therapeutics ameliorating the core symptoms of the disorder.


Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/terapia , Animais , Deleção Cromossômica , Transtornos Cromossômicos/etiologia , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 22/genética , Modelos Animais de Doenças , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
17.
Hum Mol Genet ; 24(R1): R24-31, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26188008

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication and social interaction and the presence of repetitive behaviors and/or restricted interests. ASD has profound etiological and clinical heterogeneity, which has impeded the identification of risk factors and pathophysiological processes underlying the disorder. A constellation of (i) types of genetic variation, (ii) modes of inheritance and (iii) specific genomic loci and genes have all recently been implicated in ASD risk, and these findings are currently being extended with functional analyses in model organisms and genotype-phenotype correlation studies. The overlap of risk loci between ASD and other NDDs raises intriguing questions around the mechanisms of risk. In this review, we will touch upon these aspects of ASD and how they might be addressed.


Assuntos
Transtorno do Espectro Autista/genética , Genômica , Animais , Estudos de Associação Genética , Variação Genética , Humanos , Padrões de Herança , Fatores de Risco
18.
J Neurosci ; 35(25): 9402-8, 2015 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-26109663

RESUMO

In brain, specific RNA-binding proteins (RBPs) associate with localized mRNAs and function as regulators of protein synthesis at synapses exerting an indirect control on neuronal activity. Thus, the Fragile X Mental Retardation protein (FMRP) regulates expression of the scaffolding postsynaptic density protein PSD95, but the mode of control appears to be different from other FMRP target mRNAs. Here, we show that the fragile X mental retardation-related protein 2 (FXR2P) cooperates with FMRP in binding to the 3'-UTR of mouse PSD95/Dlg4 mRNA. Absence of FXR2P leads to decreased translation of PSD95/Dlg4 mRNA in the hippocampus, implying a role for FXR2P as translation activator. Remarkably, mGluR-dependent increase of PSD95 synthesis is abolished in neurons lacking Fxr2. Together, these findings show a coordinated regulation of PSD95/Dlg4 mRNA by FMRP and FXR2P that ultimately affects its fine-tuning during synaptic activity.


Assuntos
Regulação da Expressão Gênica/fisiologia , Guanilato Quinases/biossíntese , Proteínas de Membrana/biossíntese , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Western Blotting , Proteína 4 Homóloga a Disks-Large , Guanilato Quinases/genética , Imuno-Histoquímica , Imunoprecipitação , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biossíntese de Proteínas/fisiologia , Proteínas de Ligação a RNA/genética
19.
Curr Neurol Neurosci Rep ; 15(6): 36, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25946996

RESUMO

Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder with high prevalence in the population and a pronounced male preponderance. ASD has a strong genetic basis, but until recently, a large fraction of the genetic factors contributing to liability was still unknown. Over the past 3 years, high-throughput next-generation sequencing on large cohorts has exposed a heterogeneous and complex genetic landscape and has revealed novel risk genes. Here, we provide an overview of the recent advances on the ASD genetic architecture, with an emphasis on the estimates of heritability, the contribution of common variants, and the role of inherited and de novo rare variation. We also examine the genetic components of the reported gender bias. Finally, we discuss the emerging findings from sequencing studies and how they illuminate crucial aspects of ASD pathophysiology.


Assuntos
Transtorno do Espectro Autista/genética , Animais , Variações do Número de Cópias de DNA , Exoma , Predisposição Genética para Doença , Genoma Humano , Humanos , Fatores de Risco
20.
Hum Mol Genet ; 24(14): 4006-23, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25882707

RESUMO

Despite significant progress in the genetics of autism spectrum disorder (ASD), how genetic mutations translate to the behavioral changes characteristic of ASD remains largely unknown. ASD affects 1-2% of children and adults, and is characterized by deficits in verbal and non-verbal communication, and social interactions, as well as the presence of repetitive behaviors and/or stereotyped interests. ASD is clinically and etiologically heterogeneous, with a strong genetic component. Here, we present functional data from syngap1 and shank3 zebrafish loss-of-function models of ASD. SYNGAP1, a synaptic Ras GTPase activating protein, and SHANK3, a synaptic scaffolding protein, were chosen because of mounting evidence that haploinsufficiency in these genes is highly penetrant for ASD and intellectual disability (ID). Orthologs of both SYNGAP1 and SHANK3 are duplicated in the zebrafish genome and we find that all four transcripts (syngap1a, syngap1b, shank3a and shank3b) are expressed at the earliest stages of nervous system development with pronounced expression in the larval brain. Consistent with early expression of these genes, knockdown of syngap1b or shank3a cause common embryonic phenotypes including delayed mid- and hindbrain development, disruptions in motor behaviors that manifest as unproductive swim attempts, and spontaneous, seizure-like behaviors. Our findings indicate that both syngap1b and shank3a play novel roles in morphogenesis resulting in common brain and behavioral phenotypes.


Assuntos
Transtorno do Espectro Autista/genética , Encéfalo/embriologia , Proteínas Ativadoras de GTPase/genética , Proteínas do Tecido Nervoso/genética , Organogênese/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Proteínas Ativadoras de ras GTPase/genética , Animais , Bases de Dados Genéticas , Desenvolvimento Embrionário , Proteínas Ativadoras de GTPase/metabolismo , Duplicação Gênica , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Haploinsuficiência , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo
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