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Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family / A. C. POOPAL in Molecular Autism, 7 (2016)
[article]
Titre : Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family Type de document : Texte imprimé et/ou numérique Auteurs : A. C. POOPAL, Auteur ; L. M. SCHROEDER, Auteur ; P. S. HORN, Auteur ; Gary J. BASSELL, Auteur ; C. GROSS, Auteur Article en page(s) : 3p. Langues : Anglais (eng) Mots-clés : Adenine/analogs & derivatives/pharmacology Autistic Disorder/enzymology/genetics/pathology Biomarkers Cell Line Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors/biosynthesis/genetics/physiology Diseases in Twins Enzyme-Linked Immunosorbent Assay Family Health Female Humans Lymphocytes/enzymology Male Molecular Targeted Therapy Nerve Tissue Proteins/genetics/metabolism Phosphorylation Protein Processing, Post-Translational Quinazolines/pharmacology Ribosomal Protein S6 Kinases/metabolism Signal Transduction/genetics TOR Serine-Threonine Kinases/physiology Autism Biomarker Ic87114 PI3K/mTOR signaling S6 phosphorylation p110delta Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. METHODS: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. RESULTS: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110delta, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110delta-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. CONCLUSIONS: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110delta as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110delta activity was recently associated with schizophrenia, and our results suggest that p110delta may also be implicated in autism. En ligne : http://dx.doi.org/10.1186/s13229-015-0066-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329
in Molecular Autism > 7 (2016) . - 3p.[article] Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family [Texte imprimé et/ou numérique] / A. C. POOPAL, Auteur ; L. M. SCHROEDER, Auteur ; P. S. HORN, Auteur ; Gary J. BASSELL, Auteur ; C. GROSS, Auteur . - 3p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 3p.
Mots-clés : Adenine/analogs & derivatives/pharmacology Autistic Disorder/enzymology/genetics/pathology Biomarkers Cell Line Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors/biosynthesis/genetics/physiology Diseases in Twins Enzyme-Linked Immunosorbent Assay Family Health Female Humans Lymphocytes/enzymology Male Molecular Targeted Therapy Nerve Tissue Proteins/genetics/metabolism Phosphorylation Protein Processing, Post-Translational Quinazolines/pharmacology Ribosomal Protein S6 Kinases/metabolism Signal Transduction/genetics TOR Serine-Threonine Kinases/physiology Autism Biomarker Ic87114 PI3K/mTOR signaling S6 phosphorylation p110delta Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. METHODS: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. RESULTS: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110delta, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110delta-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. CONCLUSIONS: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110delta as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110delta activity was recently associated with schizophrenia, and our results suggest that p110delta may also be implicated in autism. En ligne : http://dx.doi.org/10.1186/s13229-015-0066-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 Autism spectrum disorder and obstetric optimality: a twin study and meta-analysis of sibling studies / S. GÓMEZ-VALLEJO in Journal of Child Psychology and Psychiatry, 62-11 (November 2021)
[article]
Titre : Autism spectrum disorder and obstetric optimality: a twin study and meta-analysis of sibling studies Type de document : Texte imprimé et/ou numérique Auteurs : S. GÓMEZ-VALLEJO, Auteur ; M. LEONI, Auteur ; A. RONALD, Auteur ; E. COLVERT, Auteur ; Francesca HAPPE, Auteur ; Patrick BOLTON, Auteur Article en page(s) : p.1353-1362 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/etiology/genetics Autistic Disorder Child Diseases in Twins Female Humans Infant, Newborn Pregnancy Siblings Twins Autism spectrum disorder genetics obstetric complications Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Recent studies have suggested that its aetiology is also influenced by environmental factors. Some of the most examined environmental factors are obstetric complications. However, the results are inconsistent. METHODS: We aimed to explore the association between obstetric complications and autism in a population-based twin sample using the Obstetric Enquiry Scale (OES), a scale that measures the presence or absence of pre-, peri- and neonatal factors. Additionally, we report the meta-analytic results for obstetrical factors reported in previously published sibling studies. RESULTS: Our study included 115 cases pairs and 62 controls pairs and showed that children with autism and their unaffected co-twins present significantly more obstetric complications than controls (ASD vs. controls ? 1.26, CI 95% 1.11-1.40 p < .001; unaffected co-twin vs. controls ? 1.20, 95% CI 1.07-1.36 p < .003). However, we did not find statistically significant differences between children with ASD and their unaffected co-twins (? .96, 95% CI 0.85-1.09, p 0.55). Meta-analysis demonstrated that maternal hypertension (RR 1.35, CI 95% 1.23-1.48), uterine bleeding (RR 1.20 CI 95% 1.01-1.42) and exposure to antibiotic during pregnancy (1.11 CI 95% 1.00-1.22) increase risk of ASD. CONCLUSIONS: This study confirms that children with ASD and their unaffected twins show more obstetric complications than controls. However, these complications do not distinguish between ASD twins and their unaffected co-twins. In addition, the meta-analysis showed little influence of birth factors on ASD which suggests a shared familial liability for both obstetric complications and autism, rather than a causal association. En ligne : http://dx.doi.org/10.1111/jcpp.13526 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=456
in Journal of Child Psychology and Psychiatry > 62-11 (November 2021) . - p.1353-1362[article] Autism spectrum disorder and obstetric optimality: a twin study and meta-analysis of sibling studies [Texte imprimé et/ou numérique] / S. GÓMEZ-VALLEJO, Auteur ; M. LEONI, Auteur ; A. RONALD, Auteur ; E. COLVERT, Auteur ; Francesca HAPPE, Auteur ; Patrick BOLTON, Auteur . - p.1353-1362.
Langues : Anglais (eng)
in Journal of Child Psychology and Psychiatry > 62-11 (November 2021) . - p.1353-1362
Mots-clés : Autism Spectrum Disorder/etiology/genetics Autistic Disorder Child Diseases in Twins Female Humans Infant, Newborn Pregnancy Siblings Twins Autism spectrum disorder genetics obstetric complications Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Recent studies have suggested that its aetiology is also influenced by environmental factors. Some of the most examined environmental factors are obstetric complications. However, the results are inconsistent. METHODS: We aimed to explore the association between obstetric complications and autism in a population-based twin sample using the Obstetric Enquiry Scale (OES), a scale that measures the presence or absence of pre-, peri- and neonatal factors. Additionally, we report the meta-analytic results for obstetrical factors reported in previously published sibling studies. RESULTS: Our study included 115 cases pairs and 62 controls pairs and showed that children with autism and their unaffected co-twins present significantly more obstetric complications than controls (ASD vs. controls ? 1.26, CI 95% 1.11-1.40 p < .001; unaffected co-twin vs. controls ? 1.20, 95% CI 1.07-1.36 p < .003). However, we did not find statistically significant differences between children with ASD and their unaffected co-twins (? .96, 95% CI 0.85-1.09, p 0.55). Meta-analysis demonstrated that maternal hypertension (RR 1.35, CI 95% 1.23-1.48), uterine bleeding (RR 1.20 CI 95% 1.01-1.42) and exposure to antibiotic during pregnancy (1.11 CI 95% 1.00-1.22) increase risk of ASD. CONCLUSIONS: This study confirms that children with ASD and their unaffected twins show more obstetric complications than controls. However, these complications do not distinguish between ASD twins and their unaffected co-twins. In addition, the meta-analysis showed little influence of birth factors on ASD which suggests a shared familial liability for both obstetric complications and autism, rather than a causal association. En ligne : http://dx.doi.org/10.1111/jcpp.13526 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=456 Effect of co-twin gender on neurodevelopmental symptoms: a twin register study / J. M. ERIKSSON in Molecular Autism, 7 (2016)
[article]
Titre : Effect of co-twin gender on neurodevelopmental symptoms: a twin register study Type de document : Texte imprimé et/ou numérique Auteurs : J. M. ERIKSSON, Auteur ; S. LUNDSTRÖM, Auteur ; P. LICHTENSTEIN, Auteur ; Susanne BEJEROT, Auteur ; E. ERIKSSON, Auteur Article en page(s) : 8p. Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics/physiopathology Autism Spectrum Disorder/genetics/physiopathology Child Comorbidity Diseases in Twins Female Follow-Up Studies Gender Identity Humans Interview, Psychological Male Neurodevelopmental Disorders/genetics/physiopathology Parents Pregnancy Prenatal Exposure Delayed Effects Sex Characteristics Stereotyped Behavior Sweden/epidemiology Testosterone/physiology Tic Disorders/genetics/physiopathology Twins, Dizygotic/psychology Asperger syndrome Attention-deficit hyperactivity disorders Autistic disorder Symptom assessment Twin study Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders thought to have both genetic and environmental causes. It has been hypothesized that exposure to elevated levels of prenatal testosterone is associated with elevated traits of ASD and ADHD. Assuming that testosterone levels from a dizygotic male twin fetus may lead to enhanced testosterone exposure of its co-twins, we aimed to test the prenatal testosterone hypothesis by comparing same-sex with opposite-sex dizygotic twins with respect to neurodevelopmental symptoms. METHODS: Neuropsychiatric traits were assessed in a population-based twin cohort from the Child and Adolescent Twin Study in Sweden (CATSS). Parental interviews were conducted for 16,312 dizygotic twins, 9 and 12 years old, with the Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC). RESULTS: Girls with a female co-twin had an increased risk of reaching the cut-off score for ADHD compared with girls with a male co-twin. Both boys and girls with a female co-twin displayed a larger number of traits related to attention deficit and repetitive and stereotyped behaviors than those with a male twin. In girls, this also extended to social interaction and the combined measures for ASD and ADHD, however, with small effect sizes. CONCLUSIONS: Our results are reverse to what would have been expected from the prenatal testosterone hypothesis but consistent with a previous study of ASD and ADHD traits in dizygotic twins. The seemingly protective effect for girls of having a twin brother may be an effect of parent report bias, but may also be an unexpected effect of sharing the intrauterine environment with a male co-twin. En ligne : http://dx.doi.org/10.1186/s13229-016-0074-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 8p.[article] Effect of co-twin gender on neurodevelopmental symptoms: a twin register study [Texte imprimé et/ou numérique] / J. M. ERIKSSON, Auteur ; S. LUNDSTRÖM, Auteur ; P. LICHTENSTEIN, Auteur ; Susanne BEJEROT, Auteur ; E. ERIKSSON, Auteur . - 8p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 8p.
Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics/physiopathology Autism Spectrum Disorder/genetics/physiopathology Child Comorbidity Diseases in Twins Female Follow-Up Studies Gender Identity Humans Interview, Psychological Male Neurodevelopmental Disorders/genetics/physiopathology Parents Pregnancy Prenatal Exposure Delayed Effects Sex Characteristics Stereotyped Behavior Sweden/epidemiology Testosterone/physiology Tic Disorders/genetics/physiopathology Twins, Dizygotic/psychology Asperger syndrome Attention-deficit hyperactivity disorders Autistic disorder Symptom assessment Twin study Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders thought to have both genetic and environmental causes. It has been hypothesized that exposure to elevated levels of prenatal testosterone is associated with elevated traits of ASD and ADHD. Assuming that testosterone levels from a dizygotic male twin fetus may lead to enhanced testosterone exposure of its co-twins, we aimed to test the prenatal testosterone hypothesis by comparing same-sex with opposite-sex dizygotic twins with respect to neurodevelopmental symptoms. METHODS: Neuropsychiatric traits were assessed in a population-based twin cohort from the Child and Adolescent Twin Study in Sweden (CATSS). Parental interviews were conducted for 16,312 dizygotic twins, 9 and 12 years old, with the Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC). RESULTS: Girls with a female co-twin had an increased risk of reaching the cut-off score for ADHD compared with girls with a male co-twin. Both boys and girls with a female co-twin displayed a larger number of traits related to attention deficit and repetitive and stereotyped behaviors than those with a male twin. In girls, this also extended to social interaction and the combined measures for ASD and ADHD, however, with small effect sizes. CONCLUSIONS: Our results are reverse to what would have been expected from the prenatal testosterone hypothesis but consistent with a previous study of ASD and ADHD traits in dizygotic twins. The seemingly protective effect for girls of having a twin brother may be an effect of parent report bias, but may also be an unexpected effect of sharing the intrauterine environment with a male co-twin. En ligne : http://dx.doi.org/10.1186/s13229-016-0074-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 Etiological influences on the stability of autistic traits from childhood to early adulthood: evidence from a twin study / M. J. TAYLOR in Molecular Autism, 8 (2017)
[article]
Titre : Etiological influences on the stability of autistic traits from childhood to early adulthood: evidence from a twin study Type de document : Texte imprimé et/ou numérique Auteurs : M. J. TAYLOR, Auteur ; C. GILLBERG, Auteur ; P. LICHTENSTEIN, Auteur ; S. LUNDSTRÖM, Auteur Article en page(s) : 5p. Langues : Anglais (eng) Mots-clés : Adolescent Autistic Disorder/*genetics/*psychology Child Diseases in Twins Female Humans Longitudinal Studies Male Phenotype Surveys and Questionnaires Twins/*genetics *Adulthood *Autism *Genetics *Stability *Twin study Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are persistent and lifelong conditions. Despite this, almost all twin studies focus on childhood. This twin study investigated the stability of autistic traits from childhood to early adulthood and explored the degree to which any stability could be explained by genetic or environmental factors. METHODS: Parents of over 2500 twin pairs completed questionnaires assessing autistic traits when twins were aged either 9 or 12 years and again when twins were aged 18. Bivariate twin analysis assessed the degree of phenotypic and etiological stability in autistic traits across this period. Genetic overlap in autistic traits across development was also tested in individuals displaying a broad ASD phenotype, defined as scoring within the highest 5% of the sample. RESULTS: Autistic traits displayed moderate phenotypic stability (r = .39). The heritability of autistic traits was 76-77% in childhood and 60-62% in adulthood. A moderate degree of genetic influences on childhood autistic traits were carried across into adulthood (genetic correlation = .49). The majority (85%) of the stability in autistic traits was attributable to genetic factors. Genetic influences on autistic traits were moderately stable from childhood to early adulthood at the extremes (genetic correlation = .64). CONCLUSIONS: Broad autistic traits display moderate phenotypic and etiological stability from childhood to early adulthood. Genetic factors accounted for almost all phenotypic stability, although there was some phenotypic and etiological instability in autistic traits. Thus, autistic traits in adulthood are influenced by a combination of enduring and unique genetic factors. En ligne : http://dx.doi.org/10.1186/s13229-017-0120-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 5p.[article] Etiological influences on the stability of autistic traits from childhood to early adulthood: evidence from a twin study [Texte imprimé et/ou numérique] / M. J. TAYLOR, Auteur ; C. GILLBERG, Auteur ; P. LICHTENSTEIN, Auteur ; S. LUNDSTRÖM, Auteur . - 5p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 5p.
Mots-clés : Adolescent Autistic Disorder/*genetics/*psychology Child Diseases in Twins Female Humans Longitudinal Studies Male Phenotype Surveys and Questionnaires Twins/*genetics *Adulthood *Autism *Genetics *Stability *Twin study Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are persistent and lifelong conditions. Despite this, almost all twin studies focus on childhood. This twin study investigated the stability of autistic traits from childhood to early adulthood and explored the degree to which any stability could be explained by genetic or environmental factors. METHODS: Parents of over 2500 twin pairs completed questionnaires assessing autistic traits when twins were aged either 9 or 12 years and again when twins were aged 18. Bivariate twin analysis assessed the degree of phenotypic and etiological stability in autistic traits across this period. Genetic overlap in autistic traits across development was also tested in individuals displaying a broad ASD phenotype, defined as scoring within the highest 5% of the sample. RESULTS: Autistic traits displayed moderate phenotypic stability (r = .39). The heritability of autistic traits was 76-77% in childhood and 60-62% in adulthood. A moderate degree of genetic influences on childhood autistic traits were carried across into adulthood (genetic correlation = .49). The majority (85%) of the stability in autistic traits was attributable to genetic factors. Genetic influences on autistic traits were moderately stable from childhood to early adulthood at the extremes (genetic correlation = .64). CONCLUSIONS: Broad autistic traits display moderate phenotypic and etiological stability from childhood to early adulthood. Genetic factors accounted for almost all phenotypic stability, although there was some phenotypic and etiological instability in autistic traits. Thus, autistic traits in adulthood are influenced by a combination of enduring and unique genetic factors. En ligne : http://dx.doi.org/10.1186/s13229-017-0120-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331