RESUMEN
BACKGROUND: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. CASE PRESENTATION: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. CONCLUSIONS: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Síndrome del Ovario Poliquístico , Riñón Único , Humanos , Femenino , Adolescente , Trastorno del Espectro Autista/genética , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/diagnóstico , Discapacidad Intelectual/genética , Riñón Único/complicaciones , Secuenciación del Exoma , Proteínas del Tejido Nervioso/genética , Proteínas de Homeodominio/genética , Cardiopatías , Facies , Trastornos del NeurodesarrolloRESUMEN
Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.
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Trastorno del Espectro Autista , Histona Demetilasas con Dominio de Jumonji , Ratones Noqueados , Transmisión Sináptica , Animales , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Transmisión Sináptica/genética , Trastorno del Espectro Autista/genética , Ratones , Encéfalo/metabolismo , Plasticidad Neuronal/genética , Conducta Animal , Hipocampo/metabolismo , Epigénesis Genética , Masculino , Sinapsis/metabolismoRESUMEN
Human mutations of ADNP and ADNP2 are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated adnp and adnp2 mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of adnpa-/-; adnpb-/- and adnp2a-/-; adnp2b-/- larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of adnp and adnp2 resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in adnp and adnp2 mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of adnp and adnp2 in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.
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Mutación , Proteínas del Tejido Nervioso , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Disruptores Endocrinos/toxicidad , Trastorno del Espectro Autista/genética , Sistemas CRISPR-Cas , Interacción Gen-Ambiente , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/inducido químicamente , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismoRESUMEN
BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.
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Trastorno del Espectro Autista , Estudio de Asociación del Genoma Completo , Humanos , Trastorno del Espectro Autista/genética , Herencia Multifactorial , Predisposición Genética a la Enfermedad , Masculino , Femenino , Genotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression. Conditional Chd8 deletion in astrocytes, but not microglia, suppresses reactive gliosis by impeding astrocyte proliferation and morphological elaboration. Astrocyte Chd8 ablation alleviates lipopolysaccharide-induced neuroinflammation and septic-associated hypothermia in mice. Astrocytic CHD8 plays an important role in neuroinflammation by altering the chromatin landscape, regulating metabolic and lipid-associated pathways, and astrocyte-microglia crosstalk. Moreover, we show that reactive gliosis can be directly mitigated in vivo using an adeno-associated virus (AAV)-mediated Chd8 gene editing strategy. These findings uncover a role of ASD-associated CHD8 in the adult brain, which may warrant future exploration of targeting chromatin remodelers in reactive gliosis and neuroinflammation in injury and neurological diseases.
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Astrocitos , Gliosis , Animales , Gliosis/patología , Gliosis/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Ratones , Cromatina/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Ensamble y Desensamble de Cromatina , Microglía/metabolismo , Microglía/patología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones Endogámicos C57BL , Lipopolisacáridos/farmacología , Humanos , Ratones Noqueados , Masculino , Proliferación CelularRESUMEN
The human 16p11.2 chromosomal region is rich in segmental duplications which mediate the formation of recurrent CNVs. CNVs affecting the 16p11.2 region are associated with an increased risk for developing neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID), as well as abnormal body weight and head circumference and dysmorphic features, with marked phenotypic variability and reduced penetrance. CNVs affecting the 16p11.2 region mainly affect a distal interval of ~220 Kb, between Breakpoints 2 and 3 (BP2-BP3), and a proximal interval of ~593 Kb (BP4-BP5). Here, we report on 15 patients with recurrent 16p11.2 rearrangements that were identified among a cohort of 1600 patients (0.9%) with neurodevelopmental disorders. A total of 13 deletions and two duplications were identified, of which eight deletions included the proximal 16p11.2 region (BP4-BP5) and five included the distal 16p11.2 region (BP2-BP3). Of the two duplications that were identified, one affected the proximal and one the distal 16p11.2 region; however, both patients had additional CNVs contributing to phenotypic severity. The features observed and their severity varied greatly, even between patients within the same family. This article aims to further delineate the clinical spectrum of patients with 16p11.2 recurrent rearrangements in order to aid the counselling of patients and their families.
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Cromosomas Humanos Par 16 , Discapacidad Intelectual , Fenotipo , Humanos , Cromosomas Humanos Par 16/genética , Masculino , Femenino , Niño , Adolescente , Preescolar , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Variaciones en el Número de Copia de ADN , Deleción Cromosómica , Adulto , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Aberraciones Cromosómicas , Adulto JovenRESUMEN
Autistic spectrum disorder (ASD) is a neurodevelopmental disability characterised by the impairment of social interaction and communication ability. The alarming increase in its prevalence in children urged researchers to obtain a better understanding of the causes of this disease. Genetic factors are considered to be crucial, as ASD has a tendency to run in families. In recent years, with technological advances, the importance of structural variations (SVs) in ASD began to emerge. Most of these studies, however, focus on the Caucasian population. As a populated ethnicity, ASD shall be a significant health issue in China. This systematic review aims to summarise current case-control studies of SVs associated with ASD in the Chinese population. A list of genes identified in the nine included studies is provided. It also reveals that similar research focusing on other genetic backgrounds is demanded to manifest the disease etiology in different ethnic groups, and assist the development of accurate ethnic-oriented genetic diagnosis.
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Trastorno del Espectro Autista , Humanos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/epidemiología , China/epidemiología , Estudios de Casos y Controles , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Niño , Pueblos del Este de AsiaRESUMEN
Autism spectrum disorder (ASD) comprises a complex neurodevelopmental condition characterized by an impairment in social interaction, involving communication deficits and specific patterns of behaviors, like repetitive behaviors. ASD is clinically diagnosed and usually takes time, typically occurring not before four years of age. Genetic mutations affecting synaptic transmission, such as neuroligin and neurexin, are associated with ASD and contribute to behavioral and cognitive deficits. Recent research highlights the role of astrocytes, the brain's most abundant glial cells, in ASD pathology. Aberrant Ca2+ signaling in astrocytes is linked to behavioral deficits and neuroinflammation. Notably, the cytokine IL-6 overexpression by astrocytes impacts synaptogenesis. Altered neurotransmitter levels, disruptions in the blood-brain barrier, and cytokine dysregulation further contribute to ASD complexity. Understanding these astrocyte-related mechanisms holds promise for identifying ASD subtypes and developing targeted therapies.
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Astrocitos , Trastorno del Espectro Autista , Neuronas , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Humanos , Astrocitos/metabolismo , Neuronas/metabolismo , Animales , Transmisión Sináptica , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismoRESUMEN
Postmortem studies have revealed that brains of individuals with autism spectrum disorder (ASD) exhibit abnormalities in various components of the cholinergic system including cholinergic receptors, projections, and nuclei. Deletions in the 15q13.3 region which encompasses CHRNA7, the gene that encodes the α7-nACh receptor, have been linked to various neurodevelopmental disorders, including ASD. In addition, the involvement of α7-nACh receptors in biological phenomena known to play a role in the pathophysiology of ASD such as cognitive functions, learning, memory, neuroinflammation, and oxidative stress, as well as the excitation-inhibition balance in neuronal circuits and maternal immune activation have been reported in previous studies. Furthermore, evolving preclinical and clinical literature supports the potential therapeutic benefits of using selectively acting cholinergic compounds, particularly those targeting the α7-nACh receptor subtype, in the treatment of ASD. This study reviews the previous literature on the involvement of nACh receptors in the pathophysiology of ASD and focuses on the α7-nACh receptor as a potential therapeutic target.
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Trastorno del Espectro Autista , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Humanos , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/genética , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/patologíaRESUMEN
One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.
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Trastorno del Espectro Autista , Trastorno Autístico , Encéfalo , Modelos Animales de Enfermedad , Proteoma , Proteómica , Animales , Proteoma/metabolismo , Ratones , Humanos , Encéfalo/metabolismo , Proteómica/métodos , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Fenotipo , Edición Génica , Masculino , Predisposición Genética a la Enfermedad , Ratones Endogámicos C57BL , Femenino , Sistemas CRISPR-CasRESUMEN
Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
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Trastorno del Espectro Autista , Cerebelo , Ratones Noqueados , Células de Purkinje , Animales , Ratones , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Células de Purkinje/metabolismo , Cerebelo/metabolismo , Conducta Animal/fisiología , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Modelos Animales de Enfermedad , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , MasculinoRESUMEN
Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.
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Aromatasa , Trastorno del Espectro Autista , Compuestos de Bencidrilo , Encéfalo , Metilación de ADN , Ratones Noqueados , Fenoles , Efectos Tardíos de la Exposición Prenatal , Animales , Aromatasa/metabolismo , Aromatasa/genética , Masculino , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/inducido químicamente , Compuestos de Bencidrilo/toxicidad , Femenino , Fenoles/toxicidad , Embarazo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones , Humanos , Metilación de ADN/efectos de los fármacos , Fenotipo , Modelos Animales de Enfermedad , Regiones Promotoras Genéticas , PreescolarRESUMEN
Mutations in the human PCDH19 gene lead to epileptic encephalopathy of early childhood. It is characterized by the early onset of serial seizures, cognitive impairment and behavioral disorders (including autistic personality traits). In most cases, difficulties arise in selecting therapy due to pharmacoresistance. The pathogenesis of the disease is complex. The data available to us at the moment from numerous studies present the pathogenesis of «PCDH19 syndrome¼ as multi-level, affecting both the epigenetic support of cell life, and development of stem cells and progenitor cells in the process of neuroontogenesis, and the influence on the neurotransmitter mechanisms of the brain, and disruption of the formation of neural networks with an inevitable increase in the excitability of the cerebral cortex as a whole, and local changes in the highly labile regulatory structures of the hippocampal region. And it is not surprising that all these changes entail not only (and perhaps not so much) epileptization, but a profound disruption of the regulation of brain activity, accompanied by autism spectrum disorders, more profound disorders in the form of schizophrenia or cyclothymia, and the formation of delayed psychomotor development. A «side branch¼ of these pathogenetic processes can also be considered the participation of PCDH19 dysfunctions in certain variants of oncogenesis. The need for polypharmacy (in most cases) confirms the diversity of mechanisms involved in the pathogenesis of the disease and makes the prospects for the development of effective and rational treatment regimens very vague. Cautious optimism is caused only by attempts at relatively specific treatment with ganaxolone.
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Epilepsia , Polifarmacia , Humanos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/tratamiento farmacológico , Encéfalo , Cadherinas/genética , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Mutación , ProtocadherinasRESUMEN
We previously identified a unique genetic feature of Autism Spectrum Disorder (ASD) in human patients and established mouse models, a low to very low level of six microRNAs, miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p and miR-499a-5p. We attempted to interfere experimentally in mice with two of them, miR19a-3p and miR499a-5p by microinjecting into zygote pronuclei either the complementary sequence or an excess of the microRNA. Both resulted in low levels in the tissues and sperm of the targeted microRNAs and their pri and pre precursors. This method stably modify predetermined levels of miRNAs and identify miRNA alterations that cause changes in autistic behavior and predispose the individual to an inherited disease. Excess miRNA results in single-stranded miRNA variations in both free and DNA-bound RNA (R-loop) fractions in mouse models thus appearing to affect their own transcription. Analysis of miRNAs fractions in human patients blood samples confirm low level of six microRNAs also in R-loop fractions.
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MicroARNs , Fenotipo , Animales , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Humanos , Masculino , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Femenino , Modelos Animales de Enfermedad , Embrión de Mamíferos/metabolismo , AdultoRESUMEN
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose-response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 µM) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 µM worsened survival and hatching rates, while doses of 25 µM or more altered morphology, microglial status, and larval behaviours. VPA 50 µM also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD.
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Trastorno del Espectro Autista , Modelos Animales de Enfermedad , Ácido Valproico , Pez Cebra , Animales , Ácido Valproico/farmacología , Ácido Valproico/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Larva/efectos de los fármacos , Animales Modificados Genéticamente , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Microglía/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Neurogénesis/efectos de los fármacosRESUMEN
Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.
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Percepción Auditiva , Trastorno del Espectro Autista , Modelos Animales de Enfermedad , Ratones Noqueados , Fosfohidrolasa PTEN , Caracteres Sexuales , Animales , Fosfohidrolasa PTEN/genética , Femenino , Masculino , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Percepción Auditiva/fisiología , Ratones , Electroencefalografía , Estimulación Acústica , Potenciales Evocados Auditivos/fisiología , Corteza Auditiva/fisiopatología , Corteza Auditiva/crecimiento & desarrolloRESUMEN
BACKGROUND: Copy number variants (CNVs) have become increasingly instrumental in understanding the etiology of all diseases and phenotypes, including Neurocognitive Disorders (NDs). Among the well-established regions associated with ND are small parts of chromosome 16 deletions (16p11.2) and chromosome 15 duplications (15q3). Various methods have been developed to identify associations between CNVs and diseases of interest. The majority of methods are based on statistical inference techniques. However, due to the multi-dimensional nature of the features of the CNVs, these methods are still immature. The other aspect is that regions discovered by different methods are large, while the causative regions may be much smaller. RESULTS: In this study, we propose a regularized deep learning model to select causal regions for the target disease. With the help of the proximal [20] gradient descent algorithm, the model utilizes the group LASSO concept and embraces a deep learning model in a sparsity framework. We perform the CNV analysis for 74,811 individuals with three types of brain disorders, autism spectrum disorder (ASD), schizophrenia (SCZ), and developmental delay (DD), and also perform cumulative analysis to discover the regions that are common among the NDs. The brain expression of genes associated with diseases has increased by an average of 20 percent, and genes with homologs in mice that cause nervous system phenotypes have increased by 18 percent (on average). The DECIPHER data source also seeks other phenotypes connected to the detected regions alongside gene ontology analysis. The target diseases are correlated with some unexplored regions, such as deletions on 1q21.1 and 1q21.2 (for ASD), deletions on 20q12 (for SCZ), and duplications on 8p23.3 (for DD). Furthermore, our method is compared with other machine learning algorithms. CONCLUSIONS: Our model effectively identifies regions associated with phenotypic traits using regularized deep learning. Rather than attempting to analyze the whole genome, CNVDeep allows us to focus only on the causative regions of disease.
Asunto(s)
Variaciones en el Número de Copia de ADN , Aprendizaje Profundo , Esquizofrenia , Variaciones en el Número de Copia de ADN/genética , Humanos , Esquizofrenia/genética , Trastornos Neurocognitivos/genética , Trastorno del Espectro Autista/genética , Algoritmos , Discapacidades del Desarrollo/genética , Deleción Cromosómica , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 15/genéticaRESUMEN
Objective: The relationship between diabetes mellitus (DM) and autism spectrum disorder (ASD) remains controversial. This study aimed to analyze the causal relationship between different types of DM and ASD by bidirectional Mendelian randomization (MR). Methods: Single nucleotide polymorphisms for type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and ASD were obtained from genome-wide association studies. Subsequently, inverse variance weighted, MR-Egger, and weighted median were used to test the exposure-outcome causality. Finally, MR-Egger's intercept, Cochran's Q, and leave-one-out method were used to assess horizontal pleiotropy, heterogeneity, and sensitivity of the results, respectively. Results: The positive analysis showed that T2DM was associated with an increased risk of ASD, whereas neither T1DM nor GDM was associated with the risk of ASD. The reverse analysis showed that ASD was associated with an increased risk of T2DM, while it was not associated with the risk of either T1DM or GDM. MR-Egger intercept showed no horizontal pleiotropy (p > 0.05) for these results. Cochran's Q showed no heterogeneity expect for the results of T1DM on the risk of ASD, and leave-one-out sensitivity analysis showed these results were robust. Conclusion: This MR analysis suggests that T2DM and ASD are reciprocal risk factors and that they may create an intergenerational risk cycling in female patients. Aggressive prevention and treatment of T2DM and ASD help to break the trap of this risk cycling. Additionally, this study does not support a causal relationship between T1DM and ASD, as well as GDM and ASD. And more studies are needed in the future to continue to explore the interactions and underlying mechanisms between different types of DM and ASD.
Asunto(s)
Trastorno del Espectro Autista , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/etiología , Femenino , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Embarazo , Diabetes Gestacional/genética , Diabetes Gestacional/epidemiología , Factores de Riesgo , Predisposición Genética a la Enfermedad , MasculinoRESUMEN
Marcella Birtele completed her PhD in Malin Parmar's lab at Lund University, Sweden, where her project involved characterising stem cell-derived dopaminergic neurons with the long-term goal of transplanting these neurons into patients with Parkinson's disease. She is now a postdoc at the University of Southern California, USA, where she has been using cortical organoids to explore the role of autism spectrum disorder-associated genes in neural development. Marcella was selected as one of our 2024 PI fellows, a group of researchers who will be supported by Development's Pathway to Independence Programme as they aim to secure independent positions. We spoke to Marcella to hear why she decided to apply to the programme, and how the research questions she hopes to address with her own lab will bridge her previous neurodegeneration and neural development studies.
Asunto(s)
Neuronas Dopaminérgicas , Humanos , Neuronas Dopaminérgicas/metabolismo , Enfermedad de Parkinson/genética , Historia del Siglo XXI , Historia del Siglo XX , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Animales , Organoides/metabolismoRESUMEN
The severity of autism spectrum disorder (ASD) shows wide variations, though the reason remains unclear. Vitamin D (VitD) deficiency is considered a risk factor for ASD and its supplementation was reported to reduce symptom severity. Since VitD, either synthesized in the skin or absorbed from the food, is transported to the liver by the vitamin D binding protein (DBP), we have analyzed DBP genetic polymorphisms [rs7041 (A/C), rs4588 (G/T), and rs3755967 (C/T)] affecting DBP function [Case = 411; Control = 397], levels of plasma 25(OH)D and DBP [Case = 25; Control = 26], and DBP mRNA expression [Case = 74; Control = 44] in a group of Indo-Caucasoid ASD probands and neurotypical subjects. ASD probands with rs7041'CC', rs4588 'TT', and rs3755967 'TT' genotypes exhibited higher scores for a few traits. Scores for Imitation and Listening response were also higher in the presence of the "A-T" haplotype (rs7041-rs4588). Plasma 25(OH)D and DBP levels as well as DBP mRNA expressions were significantly lower in the ASD probands as compared to the neurotypical subjects. We infer that DBP deficiency, in the presence of risk genetic variants, could be one of the reasons for the reported 25(OH)D deficiency of the ASD probands.