34 recherche sur le mot-clé 'Autism Spectrum Disorder/genetics'

Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis / Lukas S. SCHAFFER in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 46p. Titre : Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis Type de document : Texte imprimé et/ou numérique Auteurs : Lukas S. SCHAFFER, Auteur ; Sophie BREUNIG, Auteur ; Jeremy M. LAWRENCE, Auteur ; Isabelle F FOOTE, Auteur ; Andrew D. GROTZINGER, Auteur Article en page(s) : 46p. Langues : Anglais (eng) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Genetic Predisposition to Disease  Attention Deficit Disorder with Hyperactivity/genetics  Phenotype  Transcriptome  Male  Female  Child  Polymorphism, Single Nucleotide  Latent Class Analysis  Attention-deficit/hyperactivity disorder  Autism spectrum disorder  Comorbidity  Genomic SEM  Multivariate genomics  Neurodevelopmental disorders  Psychiatric genetics Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways increase the likelihood of ASD independently of ADHD. METHODS: We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and childhood-diagnosed ADHD, decomposing the genetic variance for ASD into that which is unique to ASD (uASD) and that which is shared with ADHD. We computed genetic correlations between uASD and 83 external traits to estimate genetic overlap between uASD and other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched for uASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated with uASD. RESULTS: We observed positive genetic correlations between uASD and several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability for uASD was significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated with uASD, 34 of which were novel with respect to univariate analyses. These genes were overrepresented in skin-related pathologies. LIMITATIONS: Our study was limited by summary statistics derived exclusively from individuals of European ancestry. Additionally, using data based on a general ASD diagnosis limits our ability to understand genetic factors contributing to the pronounced clinical heterogeneity in ASD. CONCLUSIONS: Our findings delineate the unique genetic underpinnings of ASD that are independent of ADHD at the genome-wide, functional, and gene expression level of analysis. In addition, we identify novel associations previously masked by their diametric effects on ADHD. Collectively, these results provide insight into the processes that make ASD biologically unique. En ligne : https://dx.doi.org/10.1186/s13229-024-00624-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis [Texte imprimé et/ou numérique] / Lukas S. SCHAFFER, Auteur ; Sophie BREUNIG, Auteur ; Jeremy M. LAWRENCE, Auteur ; Isabelle F FOOTE, Auteur ; Andrew D. GROTZINGER, Auteur . - 46p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 46p. Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Genetic Predisposition to Disease  Attention Deficit Disorder with Hyperactivity/genetics  Phenotype  Transcriptome  Male  Female  Child  Polymorphism, Single Nucleotide  Latent Class Analysis  Attention-deficit/hyperactivity disorder  Autism spectrum disorder  Comorbidity  Genomic SEM  Multivariate genomics  Neurodevelopmental disorders  Psychiatric genetics Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways increase the likelihood of ASD independently of ADHD. METHODS: We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and childhood-diagnosed ADHD, decomposing the genetic variance for ASD into that which is unique to ASD (uASD) and that which is shared with ADHD. We computed genetic correlations between uASD and 83 external traits to estimate genetic overlap between uASD and other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched for uASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated with uASD. RESULTS: We observed positive genetic correlations between uASD and several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability for uASD was significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated with uASD, 34 of which were novel with respect to univariate analyses. These genes were overrepresented in skin-related pathologies. LIMITATIONS: Our study was limited by summary statistics derived exclusively from individuals of European ancestry. Additionally, using data based on a general ASD diagnosis limits our ability to understand genetic factors contributing to the pronounced clinical heterogeneity in ASD. CONCLUSIONS: Our findings delineate the unique genetic underpinnings of ASD that are independent of ADHD at the genome-wide, functional, and gene expression level of analysis. In addition, we identify novel associations previously masked by their diametric effects on ADHD. Collectively, these results provide insight into the processes that make ASD biologically unique. En ligne : https://dx.doi.org/10.1186/s13229-024-00624-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder / W. FYKE in Autism Research, 14-9 (September 2021)  

Public ISBD [article]  inAutism Research > 14-9 (September 2021) . - p.1854-1872 Titre : Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; Valerie LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur Article en page(s) : p.1854-1872 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder [Texte imprimé et/ou numérique] / W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; Valerie LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur . - p.1854-1872. Langues : Anglais (eng) in Autism Research > 14-9 (September 2021) . - p.1854-1872 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes / Mohammed UDDIN ; Joris A VELTMAN ; Sara WELLS ; Christopher MORRIS ; Marc WOODBURY-SMITH in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 5 Titre : Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes Type de document : Texte imprimé et/ou numérique Auteurs : Mohammed UDDIN, Auteur ; Joris A VELTMAN, Auteur ; Sara WELLS, Auteur ; Christopher MORRIS, Auteur ; Marc WOODBURY-SMITH, Auteur Article en page(s) : 5 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Humans  Macaca mulatta/genetics  Evolution, Molecular  Genome  Phenotype  Genetic Predisposition to Disease  Primates/genetics  Autism spectrum disorder  Gsea  Genetic constraint  Primate model  Whole genome sequencing  mGAP database protocols adhered to the NIH and the Guide for Use and Care of  Laboratory Animals and were approved by the Oregon Health & Sciences University  Animal Utilization and Care Committee [22]. Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Significant progress has been made in elucidating the genetic underpinnings of Autism Spectrum Disorder (ASD). However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. METHODS: We used the macaque Genotype and Phenotype (mGAP) resource consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. RESULTS: We demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-associated genes exhibit significant constraint in macaques (p = 9.4?*?10(-?27)). Among macaques, many key ASD-implicated genes were observed to harbour predicted damaging mutations. A small number of key ASD-implicated genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes associated with intellectual disability (p = 1.1?*?10(-?46)), epilepsy (p = 2.1?*?10(-?33)) and schizophrenia (p = 4.2?*?10(-?45)), and for an overlapping neurodevelopmental gene set (p = 4.0?*?10(-?10)). LIMITATIONS: The lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. CONCLUSION: The presence of pathological mutations in ASD genes among macaques, along with evidence of similar genetic constraints to those in humans, provides a strong rationale for further investigation of genotype-phenotype relationships in macaques. This highlights the importance of developing primate models of ASD to elucidate the neurobiological underpinnings and advance approaches for precision medicine and therapeutic interventions. En ligne : https://dx.doi.org/10.1186/s13229-024-00633-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes [Texte imprimé et/ou numérique] / Mohammed UDDIN, Auteur ; Joris A VELTMAN, Auteur ; Sara WELLS, Auteur ; Christopher MORRIS, Auteur ; Marc WOODBURY-SMITH, Auteur . - 5. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 5 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Humans  Macaca mulatta/genetics  Evolution, Molecular  Genome  Phenotype  Genetic Predisposition to Disease  Primates/genetics  Autism spectrum disorder  Gsea  Genetic constraint  Primate model  Whole genome sequencing  mGAP database protocols adhered to the NIH and the Guide for Use and Care of  Laboratory Animals and were approved by the Oregon Health & Sciences University  Animal Utilization and Care Committee [22]. Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Significant progress has been made in elucidating the genetic underpinnings of Autism Spectrum Disorder (ASD). However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. METHODS: We used the macaque Genotype and Phenotype (mGAP) resource consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. RESULTS: We demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-associated genes exhibit significant constraint in macaques (p = 9.4?*?10(-?27)). Among macaques, many key ASD-implicated genes were observed to harbour predicted damaging mutations. A small number of key ASD-implicated genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes associated with intellectual disability (p = 1.1?*?10(-?46)), epilepsy (p = 2.1?*?10(-?33)) and schizophrenia (p = 4.2?*?10(-?45)), and for an overlapping neurodevelopmental gene set (p = 4.0?*?10(-?10)). LIMITATIONS: The lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. CONCLUSION: The presence of pathological mutations in ASD genes among macaques, along with evidence of similar genetic constraints to those in humans, provides a strong rationale for further investigation of genotype-phenotype relationships in macaques. This highlights the importance of developing primate models of ASD to elucidate the neurobiological underpinnings and advance approaches for precision medicine and therapeutic interventions. En ligne : https://dx.doi.org/10.1186/s13229-024-00633-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder / T. SAELIW in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 27p. Titre : Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : T. SAELIW, Auteur ; C. TANGSUWANSRI, Auteur ; S. THONGKORN, Auteur ; W. CHONCHAIYA, Auteur ; K. SUPHAPEETIPORN, Auteur ; A. MUTIRANGURA, Auteur ; T. TENCOMNAO, Auteur ; V. W. HU, Auteur ; T. SARACHANA, Auteur Article en page(s) : 27p. Langues : Anglais (eng) Mots-clés : Alu Elements  Autism Spectrum Disorder/genetics  Case-Control Studies  Cells, Cultured  DNA Methylation  Epigenesis, Genetic  Female  Gene Regulatory Networks  Genome, Human  Humans  Male  Transcriptome  Autism spectrum disorder  Epigenetic regulation  Gene expression profiles  Lymphoblastoid cell lines  Neuroinflammation  Retrotransposon  Sex bias  Subgrouping Index. décimale : PER Périodiques Résumé : Background: Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. Methods: We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. Results: In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Conclusion: Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0213-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder [Texte imprimé et/ou numérique] / T. SAELIW, Auteur ; C. TANGSUWANSRI, Auteur ; S. THONGKORN, Auteur ; W. CHONCHAIYA, Auteur ; K. SUPHAPEETIPORN, Auteur ; A. MUTIRANGURA, Auteur ; T. TENCOMNAO, Auteur ; V. W. HU, Auteur ; T. SARACHANA, Auteur . - 27p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 27p. Mots-clés : Alu Elements  Autism Spectrum Disorder/genetics  Case-Control Studies  Cells, Cultured  DNA Methylation  Epigenesis, Genetic  Female  Gene Regulatory Networks  Genome, Human  Humans  Male  Transcriptome  Autism spectrum disorder  Epigenetic regulation  Gene expression profiles  Lymphoblastoid cell lines  Neuroinflammation  Retrotransposon  Sex bias  Subgrouping Index. décimale : PER Périodiques Résumé : Background: Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. Methods: We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. Results: In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Conclusion: Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0213-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder / J. PIJUAN in Autism Research, 14-6 (June 2021)  

Public ISBD [article]  inAutism Research > 14-6 (June 2021) . - p.1088-1100 Titre : PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur Article en page(s) : p.1088-1100 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics  Autism Spectrum Disorder/genetics  DNA Copy Number Variations  Exome  Genetic Predisposition to Disease/genetics  Humans  Nerve Tissue Proteins/genetics  Receptors, Cell Surface  Lrrc40  Plxna2  autism spectrum disorder  diagnosis  neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder [Texte imprimé et/ou numérique] / J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur . - p.1088-1100. Langues : Anglais (eng) in Autism Research > 14-6 (June 2021) . - p.1088-1100 Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics  Autism Spectrum Disorder/genetics  DNA Copy Number Variations  Exome  Genetic Predisposition to Disease/genetics  Humans  Nerve Tissue Proteins/genetics  Receptors, Cell Surface  Lrrc40  Plxna2  autism spectrum disorder  diagnosis  neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

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