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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 917-920, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487544

RESUMO

Phelan-McDermid syndrome (PMS)(OMIM#606232) is a rare genetic disorder caused by a deletion of the distal long arm of chromosome 22q13 involving a variety of clinical features with considerably heterogeneous degrees of severity. This syndrome is characterized by global developmental delay, intellectual disability, hypotonia, absent or severely delayed speech, minor dysmorphic features and autism spectrum disorder. PMS is easy to be misdiagnosed due to the lack of specific clinical manifestations. SHANK3 has been identified as the critical candidate gene for the neurological features of this syndrome. However, some studies have shown that other genes located in the 22q13 region may have a role in the formation of symptoms in individuals with PMS. This article provides a review for recent progress made in research on PMS including etiology, clinical manifestation, diagnosis, and treatment, with a particular emphasis on clinical diagnosis and treatment.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22 , Humanos , Proteínas do Tecido Nervoso/genética
2.
Nat Commun ; 12(1): 4087, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471112

RESUMO

We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.


Assuntos
Transtorno do Espectro Autista/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Organoides/metabolismo , Prosencéfalo/metabolismo , Adolescente , Transtorno do Espectro Autista/genética , Diferenciação Celular , Proliferação de Células , Criança , Feminino , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Fenótipo , Análise de Sequência de RNA
3.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445048

RESUMO

This study evaluates the prevalence of autistic behaviors in fragile X syndrome as a function of infant diet. Retrospective survey data from the Fragile X Syndrome Nutrition Study, which included data on infant feeding and caregiver-reported developmental milestones for 190 children with fragile X syndrome enrolled in the Fragile X Online Registry with Accessible Database (FORWARD), were analyzed. Exploratory, sex-specific associations were found linking the use of soy-based infant formula with worse autistic behaviors related to language in females and self-injurious behavior in males. These findings prompt prospective evaluation of the effects of soy-based infant formula on disease comorbidities in fragile X syndrome, a rare disorder for which newborn screening could be implemented if there was an intervention. Gastrointestinal problems were the most common reason cited for switching to soy-based infant formula. Thus, these findings also support the study of early gastrointestinal problems in fragile X syndrome, which may underly the development and severity of disease comorbidities. In conjunction with comorbidity data from the previous analyses of the Fragile X Syndrome Nutrition Study, the findings indicate that premutation fragile X mothers should be encouraged to breastfeed.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Comportamento Alimentar/psicologia , Síndrome do Cromossomo X Frágil/psicologia , Fórmulas Infantis/estatística & dados numéricos , Fenômenos Fisiológicos da Nutrição do Lactente/genética , Adolescente , Transtorno do Espectro Autista/genética , Comorbidade , Feminino , Síndrome do Cromossomo X Frágil/fisiopatologia , Gastroenteropatias/epidemiologia , Gastroenteropatias/genética , Humanos , Lactente , Masculino , Inquéritos Nutricionais , Pais , Prevalência , Estudos Retrospectivos
4.
Artigo em Inglês | MEDLINE | ID: mdl-34444373

RESUMO

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with early onset in utero or childhood. Environmental exposure to six metals (Pb, Hg, As, Cd, Mn, Al) is believed to be associated with ASD directly or interactively with genes. Objective: To assess the association of ASD among Pakistani children with the six metals and genotype frequencies of three GST genes (GSTP1, GSTM1, GSTT1). METHODS: We enrolled 30 ASD cases, age 2-12 years old, and 30 age- and sex-matched typically developing (TD) controls in Karachi, Pakistan. We assessed associations of ASD status with various factors using Conditional Logistic Regression models. We also used General Linear Models to assess possible interaction of blood Mn and Pb concentrations with the three GST genes in relation to ASD status. RESULTS: The unadjusted difference between ASD and TD groups in terms of geometric mean blood Pb concentrations was marginally significant (p = 0.05), but for Al concentrations, the adjusted difference was marginally significant (p = 0.06). CONCLUSIONS: This is the first study reporting six blood metal concentrations of Pakistani children with ASD. Estimates provided for possible interactions of GST genes with Mn and Pb in relation to ASD status are valuable for designing future similar studies.


Assuntos
Arsênio , Transtorno do Espectro Autista , Mercúrio , Alumínio , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Cádmio , Criança , Pré-Escolar , Humanos , Chumbo , Manganês , Mercúrio/análise , Paquistão/epidemiologia
5.
Postepy Biochem ; 67(1): 28-33, 2021 03 31.
Artigo em Polonês | MEDLINE | ID: mdl-34378896

RESUMO

Autism spectrum disorder (ASD) is common early neurodevelopmental disorder characterized by a varied trajectory and symptoms which affects diagnosis and therapy. For this reason, great diagnostic and therapeutic possibilities are seen in genetic studies. The aim of this review is to discuss the genetic architecture of ASD and possible therapeutic strategies.The patterns of ASD inheritance are discussed, genetic variations (including CNV polymorphisms) and the percentage of the ASD patients divided into specific classes of genetic mutations are indicated. The paper shows the most important three basic models of inheritance: polygenic, oligogenic and main gene. Molecular and cellular mechanisms linked to neurobiological models of ASD are also presented. Genetic research confirms the diversity of genetic factors involved in the ASD formation. Model systems based on the genes of the neurodevelopmental syndrome show the ability to reverse some deficits in adult patients.


Assuntos
Transtorno do Espectro Autista , Adulto , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Humanos , Modelos Biológicos , Mutação
6.
Nat Commun ; 12(1): 4056, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210967

RESUMO

Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Comportamento Animal/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Trissomia/genética , Animais , Transtorno do Espectro Autista/metabolismo , Cromossomos Humanos Par 15/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Fenótipo
7.
BMC Psychiatry ; 21(1): 360, 2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273950

RESUMO

BACKGROUND: Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene. CASE PRESENTATION: The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant. CONCLUSIONS: The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Adolescente , Transtorno do Espectro Autista/genética , Proteínas do Citoesqueleto/genética , Feminino , Humanos , Deficiência Intelectual/genética , Pessoa de Meia-Idade , Fenótipo , Qualidade de Vida , Fatores de Transcrição/genética
8.
Neuron ; 109(14): 2212-2215, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34293291

RESUMO

Autism spectrum disorder (ASD) is a clinically and etiologically diverse developmental condition characterized by diminished social interactions, impaired communication, and repetitive and/or restrictive behaviors. Recent advances in ASD genetics pave the way for implementation of precision medicine in clinical management of autism.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Medicina de Precisão , Transtorno do Espectro Autista/genética , Humanos
9.
Behav Neurol ; 2021: 4150926, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257739

RESUMO

Objective: Genetic factors play an important role in the development of autism spectrum disorder (ASD). This case-control study was to determine the association between childhood ASD and single nucleotide polymorphisms (SNPs) rs3746599 in the DUSP15 gene, rs7794745 in the CNTNAP2 gene, and rs251379 in the PCDHA gene in a Chinese Han population. Methods: Genotypes of SNPs were examined in DNA extracted from blood cells from 201 children with ASD and 200 healthy controls. The Children Autism Rating Scale (CARS) was applied to evaluate the severity of the disease and language impairment. The relationship between SNPs and the risk of ASD or the severity of the disease was determined by logistic regression and one-way ANOVA. Results: The genotype G/G of rs3746599 in the DUSP15 gene was significantly associated with a decreased risk of ASD (odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.42-0.99, P = 0.0449). The T allele of rs7794745 in the CNTNAP2 gene was associated with an increased risk of ASD (OR = 1.34, 95% CI: 1.01-1.77, P = 0.0435). The SNP rs251379 was not associated with ASD. Though none of the SNPs examined were associated with ASD severity, rs7794745 was associated with severity of language impairment. Conclusions: Our findings suggest that both rs3746599 in the DUSP15 gene and rs7794745 in the CNTNAP2 gene are associated with risk of childhood ASD, and rs7794745 is also related to the severity of language impairment in autistic children from a Chinese Han population.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Fosfatases de Especificidade Dupla , Proteínas de Membrana , Proteínas do Tecido Nervoso , Transtorno do Espectro Autista/genética , Estudos de Casos e Controles , Criança , Fosfatases de Especificidade Dupla/genética , Predisposição Genética para Doença/genética , Humanos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética
10.
Neuroimage Clin ; 31: 102729, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34271514

RESUMO

BACKGROUNDS: Although evidence suggests that the activity of the anterior cingulate cortex involves social cognition, there are inconsistent findings regarding the aberrant cingulate gray matter (GM) and scanty evidence about altered cortical thickness and white matter (WM) of cingulate in individuals with autism spectrum disorder (ASD). Evidence supports the association between the genetic variants of CNTNAP2 and altered brain connectivity. This study investigated the cingulate substructure and its association with social awareness deficits and the CNTNAP2 variants in individuals with ASD and typically-developing controls (TDC). METHODS: We assessed 118 individuals with ASD and 122 TDC with MRI and clinical evaluation. The GM, WM volumes and cortical thickness of the cingulate gyrus were compared between ASD and TDC based on fine parcellation. Five SNPs of the CNTNAP2 linked to ASD and brain structural abnormality were genotyped, and rs2710102, rs2538991, rs2710126 passed quality control filters. RESULTS: ASD individuals showed thinner cortical thickness in bilateral cingulate subregions than TDC without significant group differences in GM and WM volumes. The WM volume of the right anterior cingulate gyrus was correlated with social awareness deficits in ASD. The CNTNAP2 variant demonstrated a main effect on the WM volumes of the right middle cingulate gyrus. Besides, the CNTNAP2 variants interacted with ASD diagnosis and age on the cortical thickness of the left anterior middle cingulate cortex. CONCLUSIONS: Our findings suggest that aberrant cingulate structure in ASD might be associated with the social awareness deficits and genetic variants of the CNTNAP2. These novel findings need validation.


Assuntos
Transtorno do Espectro Autista , Substância Branca , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/genética , Encéfalo , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Substância Branca/diagnóstico por imagem
11.
Neuropsychopharmacology ; 46(11): 2000-2010, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34239048

RESUMO

Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.


Assuntos
Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Camundongos , Serotonina , Comportamento Social
12.
Nat Genet ; 53(8): 1125-1134, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312540

RESUMO

Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin-protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Proteínas/genética , Transtorno Autístico/genética , Evolução Molecular , Dosagem de Genes , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas/genética , Irmãos , Sequenciamento Completo do Genoma
13.
J Neurodev Disord ; 13(1): 26, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246244

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability. METHODS: We used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison. RESULTS: We found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size. CONCLUSIONS: This study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Criança , Deleção Cromossômica , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22 , Feminino , Humanos , Fenótipo
14.
Nat Neurosci ; 24(9): 1243-1255, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34253921

RESUMO

Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal's own experience. This shift was associated with a loss of ability by neurons to distinguish other from self and, therefore, the inability to encode social agency. Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5-8 weeks. These findings reveal a neuronal-encoding process that is necessary for social behavior and that may be disrupted in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Comportamento Social , Animais , Transtorno do Espectro Autista/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299197

RESUMO

In recent years, accumulating evidence has shown that the innate immune complement system is involved in several aspects of normal brain development and in neurodevelopmental disorders, including autism spectrum disorder (ASD). Although abnormal expression of complement components was observed in post-mortem brain samples from individuals with ASD, little is known about the expression patterns of complement molecules in distinct cell types in the developing autistic brain. In the present study, we characterized the mRNA and protein expression profiles of a wide range of complement system components, receptors and regulators in induced pluripotent stem cell (iPSC)-derived neural progenitor cells, neurons and astrocytes of individuals with ASD and neurotypical controls, which constitute in vitro cellular models that recapitulate certain features of both human brain development and ASD pathophysiology. We observed that all the analyzed cell lines constitutively express several key complement molecules. Interestingly, using different quantification strategies, we found that complement C4 mRNA and protein are expressed in significantly lower levels by astrocytes derived from ASD individuals compared to control astrocytes. As astrocytes participate in synapse elimination, and diminished C4 levels have been linked to defective synaptic pruning, our findings may contribute to an increased understanding of the atypically enhanced brain connectivity in ASD.


Assuntos
Astrócitos/patologia , Transtorno do Espectro Autista/patologia , Complemento C4/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Neurais/patologia , Neurônios/patologia , Astrócitos/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Células Cultivadas , Complemento C4/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo
16.
Autism Res ; 14(8): 1543-1553, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245229

RESUMO

Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h2  = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Adulto , Transtorno do Espectro Autista/genética , Função Executiva , Humanos , Fenótipo , Inquéritos e Questionários
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(7): 620-625, 2021 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-34247363

RESUMO

OBJECTIVE: To analyze the pathogenic variants of the KIF1A gene and its corresponding protein structure in an autism spectrum disorder (ASD) family trio carrying harmful missense variants in the KIF1A gene. METHODS: The peripheral blood DNA of the patient and his parents was extracted and sequenced using whole exome sequencing (WES) technology and verified by Sanger sequencing. Bioinformatics software SIFT, PolyPhen-2, Mutation Taster, and CADD software were used to analyze the harmfulness and conservation of variants. The Human Brain Transcriptome (HBT) database was used to analyze the expression of the KIF1A gene in the brain. PredictProtein and SWISS-MODEL were further used to predict the secondary structure and tertiary structure of KIF1A wild-type protein and variant protein. PyMOL V2.4 was utilized to investigate the change of hydrogen bond connection after protein variant. RESULTS: The WES sequencing revealed a missense variant c.664A>C (p.Asn222His) in the child's KIF1A gene, and this variant was a de novo variant. The harmfulness prediction results suggest that this variant is harmful. By analyzing expression level of KIF1A gene in the brain. It is found that KIF1A gene widely expressed in various brain regions during embryonic development. By analyzing the variant protein structure, the missense variant of KIF1A will cause many changes in the secondary structure of protein, such as alpha-helix, beta-strand, and protein binding domain. The connection of hydrogen bond and spatial structure will also change, thereby changing the original biological function. CONCLUSION: The KIF1A gene may be a risk gene for ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno do Espectro Autista/genética , Criança , Feminino , Humanos , Cinesina/genética , Mutação , Mutação de Sentido Incorreto , Gravidez , Domínios Proteicos , Sequenciamento Completo do Exoma
18.
Neurosci Biobehav Rev ; 128: 534-548, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34216652

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral deficits including impairments in social communication, social interaction, and repetitive behaviors. Because the etiology of ASD is still largely unknown, there is no cure for ASD thus far. Although it has been established that genetic components play a vital role in ASD development, the influence of epigenetic regulation induced by environmental factors could also contribute to ASD susceptibility. Accumulated evidence has suggested that exposure to atmospheric particulate matter (PM) in polluted air could affect neurodevelopment, thus possibly leading to ASD. Particles with a size of 2.5 µm (PM2.5) or less have been shown to have negative effects on human health, and could be linked to ASD symptoms in children. This review summarizes evidence from clinical and animal studies to demonstrate the possible linkage between PM2.5 exposure and the incidence of ASD in children. An attempt was made to explore the possible mechanisms of this linkage, including changes of gene expression, oxidative stress and neuroinflammation induced by PM2.5 exposure.


Assuntos
Transtorno do Espectro Autista , Material Particulado , Animais , Transtorno do Espectro Autista/genética , Criança , Epigênese Genética , Expressão Gênica , Humanos , Estresse Oxidativo/genética , Material Particulado/toxicidade , Fatores de Risco
19.
Nat Commun ; 12(1): 4284, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257281

RESUMO

The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.


Assuntos
Transtorno do Espectro Autista/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transtorno do Espectro Autista/genética , Citosol/metabolismo , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética
20.
Nat Commun ; 12(1): 3773, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145239

RESUMO

Abnormalities in GABAergic inhibitory circuits have been implicated in the aetiology of autism spectrum disorder (ASD). ASD is caused by genetic and environmental factors. Several genes have been associated with syndromic forms of ASD, including FOXG1. However, when and how dysregulation of FOXG1 can result in defects in inhibitory circuit development and ASD-like social impairments is unclear. Here, we show that increased or decreased FoxG1 expression in both excitatory and inhibitory neurons results in ASD-related circuit and social behavior deficits in our mouse models. We observe that the second postnatal week is the critical period when regulation of FoxG1 expression is required to prevent subsequent ASD-like social impairments. Transplantation of GABAergic precursor cells prior to this critical period and reduction in GABAergic tone via Gad2 mutation ameliorates and exacerbates circuit functionality and social behavioral defects, respectively. Our results provide mechanistic insight into the developmental timing of inhibitory circuit formation underlying ASD-like phenotypes in mouse models.


Assuntos
Transtorno do Espectro Autista/genética , Encéfalo/crescimento & desenvolvimento , Fatores de Transcrição Forkhead/genética , Neurônios GABAérgicos/citologia , Proteínas do Tecido Nervoso/genética , Comportamento Social , Animais , Encéfalo/fisiologia , Modelos Animais de Doenças , Neurônios GABAérgicos/transplante , Glutamato Descarboxilase/genética , Camundongos
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