Dépouillements

The effect of intranasal oxytocin versus placebo treatment on the autonomic responses to human sounds in autism: a single-blind, randomized, placebo-controlled, crossover design study / I-Fan LIN in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : The effect of intranasal oxytocin versus placebo treatment on the autonomic responses to human sounds in autism: a single-blind, randomized, placebo-controlled, crossover design study Type de document : Texte imprimé et/ou numérique Auteurs : I-Fan LIN, Auteur ; Makio KASHINO, Auteur ; Haruhisa OHTA, Auteur ; Takashi YAMADA, Auteur ; Masayuki TANI, Auteur ; Hiromi WATANABE, Auteur ; Chieko KANAI, Auteur ; Taisei OHNO, Auteur ; Yuko TAKAYAMA, Auteur ; Akira IWANAMI, Auteur ; Nobumasa KATO, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Many individuals with autism spectrum disorders (ASD) have difficulty with verbal communication, which might be due to a lack of spontaneous orientation toward social auditory stimuli. Previous studies have shown that a single dose of oxytocin improves speech comprehension in autism. The primary aim of this study was to investigate whether the orientation behaviors toward human sounds are different for neurotypical (NT) adults and adults with ASD and whether oxytocin has an effect on their orientation behaviors toward human sounds. This was a randomized, placebo-controlled, within-subject, crossover design study of intranasal oxytocin versus placebo in 13 NT adults and 16 adults with ASD. Subjects were randomized to 24 IU intranasal oxytocin or placebo on different days, and they were blind to the treatment. The participants then listened passively to human and non-human affective sounds while their skin conductance responses (SCRs) and the changes in peripheral blood vessel constriction were monitored as an indicator of spontaneous orientation. The monitored data were analyzed by a mixed-design ANOVA. Oxytocin enhanced the difference between the SCRs to human and non-human sounds in both the NT and ASD groups (F(1,56) = 6.046, p = 0.017). Further correlation coefficient analysis showed significant correlations between this SCR difference and the scores in the autism spectrum quotient 'attention to detail' and 'social skill' subscales and interpersonal reactivity index and social functioning scale in the ASD group. Oxytocin was well tolerated, and no serious adverse effects were reported. The difference in SCRs implies that oxytocin nasal spray may enhance orientation behaviors toward human sounds in the presence of other environmental sounds in both ASD and NT adults.Trial registration: UMIN-CTR Clinical Trial, Unique trial number: UMIN000005809 En ligne : http://dx.doi.org/10.1186/2040-2392-5-20 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] The effect of intranasal oxytocin versus placebo treatment on the autonomic responses to human sounds in autism: a single-blind, randomized, placebo-controlled, crossover design study [Texte imprimé et/ou numérique] / I-Fan LIN, Auteur ; Makio KASHINO, Auteur ; Haruhisa OHTA, Auteur ; Takashi YAMADA, Auteur ; Masayuki TANI, Auteur ; Hiromi WATANABE, Auteur ; Chieko KANAI, Auteur ; Taisei OHNO, Auteur ; Yuko TAKAYAMA, Auteur ; Akira IWANAMI, Auteur ; Nobumasa KATO, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Many individuals with autism spectrum disorders (ASD) have difficulty with verbal communication, which might be due to a lack of spontaneous orientation toward social auditory stimuli. Previous studies have shown that a single dose of oxytocin improves speech comprehension in autism. The primary aim of this study was to investigate whether the orientation behaviors toward human sounds are different for neurotypical (NT) adults and adults with ASD and whether oxytocin has an effect on their orientation behaviors toward human sounds. This was a randomized, placebo-controlled, within-subject, crossover design study of intranasal oxytocin versus placebo in 13 NT adults and 16 adults with ASD. Subjects were randomized to 24 IU intranasal oxytocin or placebo on different days, and they were blind to the treatment. The participants then listened passively to human and non-human affective sounds while their skin conductance responses (SCRs) and the changes in peripheral blood vessel constriction were monitored as an indicator of spontaneous orientation. The monitored data were analyzed by a mixed-design ANOVA. Oxytocin enhanced the difference between the SCRs to human and non-human sounds in both the NT and ASD groups (F(1,56) = 6.046, p = 0.017). Further correlation coefficient analysis showed significant correlations between this SCR difference and the scores in the autism spectrum quotient 'attention to detail' and 'social skill' subscales and interpersonal reactivity index and social functioning scale in the ASD group. Oxytocin was well tolerated, and no serious adverse effects were reported. The difference in SCRs implies that oxytocin nasal spray may enhance orientation behaviors toward human sounds in the presence of other environmental sounds in both ASD and NT adults.Trial registration: UMIN-CTR Clinical Trial, Unique trial number: UMIN000005809 En ligne : http://dx.doi.org/10.1186/2040-2392-5-20 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Gender differences in emotionality and sociability in children with autism spectrum disorders / Alexandra HEAD in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Gender differences in emotionality and sociability in children with autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Alexandra HEAD, Auteur ; Jane MCGILLIVRAY, Auteur ; Mark STOKES, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Four times as many males are diagnosed with high functioning autism compared to females. A growing body of research that focused on females with autism spectrum disorder (ASD) questions the assumption of gender invariance in ASD. Clinical observations suggest that females with ASD superficially demonstrate better social and emotional skills than males with ASD, which may camouflage other diagnostic features. This may explain the under-diagnosis of females with ASD. We hypothesised that females with ASD would display better social skills than males with ASD on a test of friendship and social function. One hundred and one 10- to 16-year-olds (ASD females, n = 25; typically developing (TD) females, n = 25; ASD males, n = 25; TD males, n = 26) were interviewed (using the friendship questionnaire (FQ)) with high scores indicating the child has close, empathetic and supportive relationships. One parent of each child completed the FQ to assess whether there are differences in perception of friendships between parents and children. It was found that, independent of diagnosis, females demonstrated higher scores on the FQ than males. Further, regardless of gender, children with ASD demonstrated lower scores than TD children. Moreover, the effect of ASD was independent of gender. Interestingly, females with ASD and TD males displayed similar scores on the FQ. This finding is supported by clinical reports that females with ASD have more developed social skills than males with ASD. Further research is now required to examine the underlying causes for this phenomenon in order to develop gender-appropriate diagnostic criteria and interventions for ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Gender differences in emotionality and sociability in children with autism spectrum disorders [Texte imprimé et/ou numérique] / Alexandra HEAD, Auteur ; Jane MCGILLIVRAY, Auteur ; Mark STOKES, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Four times as many males are diagnosed with high functioning autism compared to females. A growing body of research that focused on females with autism spectrum disorder (ASD) questions the assumption of gender invariance in ASD. Clinical observations suggest that females with ASD superficially demonstrate better social and emotional skills than males with ASD, which may camouflage other diagnostic features. This may explain the under-diagnosis of females with ASD. We hypothesised that females with ASD would display better social skills than males with ASD on a test of friendship and social function. One hundred and one 10- to 16-year-olds (ASD females, n = 25; typically developing (TD) females, n = 25; ASD males, n = 25; TD males, n = 26) were interviewed (using the friendship questionnaire (FQ)) with high scores indicating the child has close, empathetic and supportive relationships. One parent of each child completed the FQ to assess whether there are differences in perception of friendships between parents and children. It was found that, independent of diagnosis, females demonstrated higher scores on the FQ than males. Further, regardless of gender, children with ASD demonstrated lower scores than TD children. Moreover, the effect of ASD was independent of gender. Interestingly, females with ASD and TD males displayed similar scores on the FQ. This finding is supported by clinical reports that females with ASD have more developed social skills than males with ASD. Further research is now required to examine the underlying causes for this phenomenon in order to develop gender-appropriate diagnostic criteria and interventions for ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence / Beate ST POURCAIN in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence Type de document : Texte imprimé et/ou numérique Auteurs : Beate ST POURCAIN, Auteur ; David SKUSE, Auteur ; William MANDY, Auteur ; Kai WANG, Auteur ; Hakon HAKONARSON, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; George DAVEY SMITH, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. Social-communication difficulties were ascertained at ages 8, 11, 14 and 17years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N[less than or equal to]5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P[less than or equal to]105) were also followed up in Autism Genetic Resource Exchange pedigrees (N=793) and the Autism Case Control cohort (Ncases/Ncontrols=1,204/6,491). GCTA heritability was strongest in childhood (h2(8 years)=0.24) and especially in later adolescence (h2(17 years)=0.45), with a marked drop during early to middle adolescence (h2(11 years)=0.16 and h2(14 years)=0.08). Genome-wide screens at ages 8 and 17years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P=9.3x109; genome-wide empirical P=0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P=7.9x108; genome-wide empirical P=0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location=0.007). Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum. En ligne : http://dx.doi.org/10.1186/2040-2392-5-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence [Texte imprimé et/ou numérique] / Beate ST POURCAIN, Auteur ; David SKUSE, Auteur ; William MANDY, Auteur ; Kai WANG, Auteur ; Hakon HAKONARSON, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; George DAVEY SMITH, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. Social-communication difficulties were ascertained at ages 8, 11, 14 and 17years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N[less than or equal to]5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P[less than or equal to]105) were also followed up in Autism Genetic Resource Exchange pedigrees (N=793) and the Autism Case Control cohort (Ncases/Ncontrols=1,204/6,491). GCTA heritability was strongest in childhood (h2(8 years)=0.24) and especially in later adolescence (h2(17 years)=0.45), with a marked drop during early to middle adolescence (h2(11 years)=0.16 and h2(14 years)=0.08). Genome-wide screens at ages 8 and 17years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P=9.3x109; genome-wide empirical P=0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P=7.9x108; genome-wide empirical P=0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location=0.007). Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum. En ligne : http://dx.doi.org/10.1186/2040-2392-5-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism / Neha UPPAL in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism Type de document : Texte imprimé et/ou numérique Auteurs : Neha UPPAL, Auteur ; Isabella GIANATIEMPO, Auteur ; Bridget WICINSKI, Auteur ; James SCHMEIDLER, Auteur ; Helmut HEINSEN, Auteur ; Christoph SCHMITZ, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : While most neuropathologic studies focus on regions involved in behavioral abnormalities in autism, it is also important to identify whether areas that appear functionally normal are devoid of pathologic alterations. In this study we analyzed the posteroinferior occipitotemporal gyrus, an extrastriate area not considered to be affected in autism. This area borders the fusiform gyrus, which is known to exhibit functional and cellular abnormalities in autism.FINDINGS:No studies have implicated posteroinferior occipitotemporal gyrus dysfunction in autism, leading us to hypothesize that neuropathology would not occur in this area. We indeed observed no significant differences in pyramidal neuron number or size in layers III, V, and VI in seven pairs of autism and controls. These findings are consistent with the hypothesis that neuropathology is unique to areas involved in stereotypies and social and emotional behaviors, and support the specificity of the localization of pathology in the fusiform gyrus. En ligne : http://dx.doi.org/10.1186/2040-2392-5-17 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism [Texte imprimé et/ou numérique] / Neha UPPAL, Auteur ; Isabella GIANATIEMPO, Auteur ; Bridget WICINSKI, Auteur ; James SCHMEIDLER, Auteur ; Helmut HEINSEN, Auteur ; Christoph SCHMITZ, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : While most neuropathologic studies focus on regions involved in behavioral abnormalities in autism, it is also important to identify whether areas that appear functionally normal are devoid of pathologic alterations. In this study we analyzed the posteroinferior occipitotemporal gyrus, an extrastriate area not considered to be affected in autism. This area borders the fusiform gyrus, which is known to exhibit functional and cellular abnormalities in autism.FINDINGS:No studies have implicated posteroinferior occipitotemporal gyrus dysfunction in autism, leading us to hypothesize that neuropathology would not occur in this area. We indeed observed no significant differences in pyramidal neuron number or size in layers III, V, and VI in seven pairs of autism and controls. These findings are consistent with the hypothesis that neuropathology is unique to areas involved in stereotypies and social and emotional behaviors, and support the specificity of the localization of pathology in the fusiform gyrus. En ligne : http://dx.doi.org/10.1186/2040-2392-5-17 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis / Sek KONG in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis Type de document : Texte imprimé et/ou numérique Auteurs : Sek KONG, Auteur ; Mustafa SAHIN, Auteur ; Christin COLLINS, Auteur ; Mary WERTZ, Auteur ; Malcolm CAMPBELL, Auteur ; Jarrett LEECH, Auteur ; Dilja D. KRUEGER, Auteur ; Mark F. BEAR, Auteur ; Louis KUNKEL, Auteur ; Isaac KOHANE, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/ mice mirror some, but not all, of the perturbed molecular pathways in the brain. En ligne : http://dx.doi.org/10.1186/2040-2392-5-16 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis [Texte imprimé et/ou numérique] / Sek KONG, Auteur ; Mustafa SAHIN, Auteur ; Christin COLLINS, Auteur ; Mary WERTZ, Auteur ; Malcolm CAMPBELL, Auteur ; Jarrett LEECH, Auteur ; Dilja D. KRUEGER, Auteur ; Mark F. BEAR, Auteur ; Louis KUNKEL, Auteur ; Isaac KOHANE, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/ mice mirror some, but not all, of the perturbed molecular pathways in the brain. En ligne : http://dx.doi.org/10.1186/2040-2392-5-16 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Rating scale measures are associated with Noldus EthoVision-XT video tracking of behaviors of children on the autism spectrum / Ira L. COHEN in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Rating scale measures are associated with Noldus EthoVision-XT video tracking of behaviors of children on the autism spectrum Type de document : Texte imprimé et/ou numérique Auteurs : Ira L. COHEN, Auteur ; Judith M. GARDNER, Auteur ; Bernard Z. KARMEL, Auteur ; Soh-Yule KIM, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Children with Autism Spectrum Disorder (ASD) show unusual social behaviors and repetitive behaviors. Some of these behaviors, e.g., time spent in an area or turning rate/direction, can be automatically tracked. Automated tracking has several advantages over subjective ratings including reliability, amount of information provided, and consistency across laboratories, and is potentially of importance for diagnosis, animal models and objective assessment of treatment efficacy. However, its validity for ASD has not been examined. In this exploratory study, we examined associations between rating scale data with automated tracking of children's movements using the Noldus EthoVision XT system; i.e., tracking not involving a human observer. Based on our observations and previous research, we predicted that time spent in the periphery of the room would be associated with autism severity and that rate and direction of turning would be associated with stereotypies. Children with and without ASD were observed in a free-play situation for 3 min before and 3 min after Autism Diagnostic Observation Scale - Generic (ADOS-G) testing. The Noldus system provided measures of the rate and direction of turning, and time spent near the periphery or the parent. Ratings of the severity of maladaptive social behaviors, stereotypies, autism severity, and arousal problems were positively correlated with increases in percent time spent in the periphery in the total sample and in the ASD subset. Adaptive social communication skills decreased with increases in the percentage of time spent in the periphery and increases in the latency to approach the parent in the ASD group. The rate and direction of turning was linked with stereotypies only in the group without ASD (the faster the rate of a turn to the left, the worse the rating). In the ASD group, there was a shift from a neutral turning bias prior to the ADOS assessment to a strong left turn bias after the ADOS assessment. In the entire sample, this left turn bias was associated with measures of autism severity.CONCLUSION:Results suggest that automated tracking yields valid and unbiased information for assessing children with autism. Turning bias is an interesting and unexplored measure related to autism. En ligne : http://dx.doi.org/10.1186/2040-2392-5-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Rating scale measures are associated with Noldus EthoVision-XT video tracking of behaviors of children on the autism spectrum [Texte imprimé et/ou numérique] / Ira L. COHEN, Auteur ; Judith M. GARDNER, Auteur ; Bernard Z. KARMEL, Auteur ; Soh-Yule KIM, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Children with Autism Spectrum Disorder (ASD) show unusual social behaviors and repetitive behaviors. Some of these behaviors, e.g., time spent in an area or turning rate/direction, can be automatically tracked. Automated tracking has several advantages over subjective ratings including reliability, amount of information provided, and consistency across laboratories, and is potentially of importance for diagnosis, animal models and objective assessment of treatment efficacy. However, its validity for ASD has not been examined. In this exploratory study, we examined associations between rating scale data with automated tracking of children's movements using the Noldus EthoVision XT system; i.e., tracking not involving a human observer. Based on our observations and previous research, we predicted that time spent in the periphery of the room would be associated with autism severity and that rate and direction of turning would be associated with stereotypies. Children with and without ASD were observed in a free-play situation for 3 min before and 3 min after Autism Diagnostic Observation Scale - Generic (ADOS-G) testing. The Noldus system provided measures of the rate and direction of turning, and time spent near the periphery or the parent. Ratings of the severity of maladaptive social behaviors, stereotypies, autism severity, and arousal problems were positively correlated with increases in percent time spent in the periphery in the total sample and in the ASD subset. Adaptive social communication skills decreased with increases in the percentage of time spent in the periphery and increases in the latency to approach the parent in the ASD group. The rate and direction of turning was linked with stereotypies only in the group without ASD (the faster the rate of a turn to the left, the worse the rating). In the ASD group, there was a shift from a neutral turning bias prior to the ADOS assessment to a strong left turn bias after the ADOS assessment. In the entire sample, this left turn bias was associated with measures of autism severity.CONCLUSION:Results suggest that automated tracking yields valid and unbiased information for assessing children with autism. Turning bias is an interesting and unexplored measure related to autism. En ligne : http://dx.doi.org/10.1186/2040-2392-5-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

STX1A and Asperger syndrome: a replication study / Jaroslava DURDIAKOVA in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : STX1A and Asperger syndrome: a replication study Type de document : Texte imprimé et/ou numérique Auteurs : Jaroslava DURDIAKOVA, Auteur ; Varun WARRIER, Auteur ; Sharmila BANERJEE-BASU, Auteur ; Simon BARON-COHEN, Auteur ; Bhismadev CHAKRABARTI, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum conditions (ASC) are a group of conditions characterized by difficulties in communication and social interaction, alongside unusually narrow interests and repetitive, stereotyped behaviour. Genetic association and expression studies have suggested an important role for the GABAergic circuits in ASC. Syntaxin 1A (STX1A) encodes a protein involved in regulation of serotonergic and GABAergic systems and its expression is altered in autism. In this study, the association between three single nucleotide polymorphisms (SNPs) (rs4717806, rs941298 and rs6951030) in STX1A gene and Asperger syndrome (AS) were tested in 650 controls and 479 individuals with AS, all of Caucasian ancestry. rs4717806 (P=0.00334) and rs941298 (P=0.01741) showed a significant association with AS, replicating previous results. Both SNPs putatively alter transcription factor binding sites both directly and through other variants in high linkage disequilibrium. The current study confirms the role of STX1A as an important candidate gene in ASC. The exact molecular mechanisms through which STX1A contributes to the etiology remain to be elucidated. En ligne : http://dx.doi.org/10.1186/2040-2392-5-14 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] STX1A and Asperger syndrome: a replication study [Texte imprimé et/ou numérique] / Jaroslava DURDIAKOVA, Auteur ; Varun WARRIER, Auteur ; Sharmila BANERJEE-BASU, Auteur ; Simon BARON-COHEN, Auteur ; Bhismadev CHAKRABARTI, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Autism spectrum conditions (ASC) are a group of conditions characterized by difficulties in communication and social interaction, alongside unusually narrow interests and repetitive, stereotyped behaviour. Genetic association and expression studies have suggested an important role for the GABAergic circuits in ASC. Syntaxin 1A (STX1A) encodes a protein involved in regulation of serotonergic and GABAergic systems and its expression is altered in autism. In this study, the association between three single nucleotide polymorphisms (SNPs) (rs4717806, rs941298 and rs6951030) in STX1A gene and Asperger syndrome (AS) were tested in 650 controls and 479 individuals with AS, all of Caucasian ancestry. rs4717806 (P=0.00334) and rs941298 (P=0.01741) showed a significant association with AS, replicating previous results. Both SNPs putatively alter transcription factor binding sites both directly and through other variants in high linkage disequilibrium. The current study confirms the role of STX1A as an important candidate gene in ASC. The exact molecular mechanisms through which STX1A contributes to the etiology remain to be elucidated. En ligne : http://dx.doi.org/10.1186/2040-2392-5-14 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder / Donna WERLING in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Donna WERLING, Auteur ; Jennifer K. LOWE, Auteur ; Rui LUO, Auteur ; Rita M. CANTOR, Auteur ; Daniel H. GESCHWIND, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE. From a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds =2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions. We observed an independent replication of previously observed linkage at chromosome 20p13 (P 0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions. With few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk. En ligne : http://dx.doi.org/10.1186/2040-2392-5-13 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder [Texte imprimé et/ou numérique] / Donna WERLING, Auteur ; Jennifer K. LOWE, Auteur ; Rui LUO, Auteur ; Rita M. CANTOR, Auteur ; Daniel H. GESCHWIND, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE. From a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds =2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions. We observed an independent replication of previously observed linkage at chromosome 20p13 (P 0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions. With few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk. En ligne : http://dx.doi.org/10.1186/2040-2392-5-13 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Individual differences in autistic traits predict the perception of direct gaze for males, but not for females / Daisuke MATSUYOSHI in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Individual differences in autistic traits predict the perception of direct gaze for males, but not for females Type de document : Texte imprimé et/ou numérique Auteurs : Daisuke MATSUYOSHI, Auteur ; Kana KURAGUCHI, Auteur ; Yumiko TANAKA, Auteur ; Seina UCHIDA, Auteur ; Hiroshi ASHIDA, Auteur ; Katsumi WATANABE, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Despite the emphasis of autism spectrum disorders as a continuum of atypical social behaviors and the sexual heterogeneity of phenotypic manifestations, whether gaze processing constitutes an autistic endophenotype in both sexes remains unclear. Using the Autism-Spectrum Quotient and a psychophysical approach in a normal population (N=128), here we demonstrated that individual differences in autistic traits predicted direct-gaze perception for males, but not for females. Our findings suggest that direct-gaze perception may not constitute an autistic endophenotype in both sexes, and highlight the importance of sex differences when considering relationships between autistic traits and behaviors. En ligne : http://dx.doi.org/10.1186/2040-2392-5-12 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Individual differences in autistic traits predict the perception of direct gaze for males, but not for females [Texte imprimé et/ou numérique] / Daisuke MATSUYOSHI, Auteur ; Kana KURAGUCHI, Auteur ; Yumiko TANAKA, Auteur ; Seina UCHIDA, Auteur ; Hiroshi ASHIDA, Auteur ; Katsumi WATANABE, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Despite the emphasis of autism spectrum disorders as a continuum of atypical social behaviors and the sexual heterogeneity of phenotypic manifestations, whether gaze processing constitutes an autistic endophenotype in both sexes remains unclear. Using the Autism-Spectrum Quotient and a psychophysical approach in a normal population (N=128), here we demonstrated that individual differences in autistic traits predicted direct-gaze perception for males, but not for females. Our findings suggest that direct-gaze perception may not constitute an autistic endophenotype in both sexes, and highlight the importance of sex differences when considering relationships between autistic traits and behaviors. En ligne : http://dx.doi.org/10.1186/2040-2392-5-12 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Behavioral signatures related to genetic disorders in autism / Hilgo BRUINING in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Behavioral signatures related to genetic disorders in autism Type de document : Texte imprimé et/ou numérique Auteurs : Hilgo BRUINING, Auteur ; Marinus EIJKEMANS, Auteur ; Martien KAS, Auteur ; Sarah CURRAN, Auteur ; Jacob VORSTMAN, Auteur ; Patrick BOLTON, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down's syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n=322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Behavioral signatures related to genetic disorders in autism [Texte imprimé et/ou numérique] / Hilgo BRUINING, Auteur ; Marinus EIJKEMANS, Auteur ; Martien KAS, Auteur ; Sarah CURRAN, Auteur ; Jacob VORSTMAN, Auteur ; Patrick BOLTON, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down's syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n=322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Protein signatures of oxidative stress response in a patient specific cell line model for autism / Andreas G. CHIOCCHETTI in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Protein signatures of oxidative stress response in a patient specific cell line model for autism Type de document : Texte imprimé et/ou numérique Auteurs : Andreas G. CHIOCCHETTI, Auteur ; Denise HASLINGER, Auteur ; Maximilian BOESCH, Auteur ; Thomas KARL, Auteur ; Stefan WIEMANN, Auteur ; Christine FREITAG, Auteur ; Fritz POUSTKA, Auteur ; Burghardt SCHEIBE, Auteur ; Johann BAUER, Auteur ; Helmut HINTNER, Auteur ; Michael BREITENBACH, Auteur ; Josef KELLERMANN, Auteur ; Friedrich LOTTSPEICH, Auteur ; Sabine M. KLAUCK, Auteur ; Lore BREITENBACH-KOLLER, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress. Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways. The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects' and the ASD patients' set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress. Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mutation RPL10[H213Q] and LCLs from ASD patients without this mutation. At pathway levels, this redox-sensitive protein signature has also been identified in a yeast rpl10 deficiency and an oxidative stress model. These observations point to a common molecular pathomechanism in ASD, characterized in our study by dysregulation of redox balance. Importantly, this can be triggered by the known ASD-RPL10[H213Q] mutation or by yet unknown mutations of the ASD cohort that act upstream of RPL10 in differential expression of redox-sensitive proteins. En ligne : http://dx.doi.org/10.1186/2040-2392-5-10 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Protein signatures of oxidative stress response in a patient specific cell line model for autism [Texte imprimé et/ou numérique] / Andreas G. CHIOCCHETTI, Auteur ; Denise HASLINGER, Auteur ; Maximilian BOESCH, Auteur ; Thomas KARL, Auteur ; Stefan WIEMANN, Auteur ; Christine FREITAG, Auteur ; Fritz POUSTKA, Auteur ; Burghardt SCHEIBE, Auteur ; Johann BAUER, Auteur ; Helmut HINTNER, Auteur ; Michael BREITENBACH, Auteur ; Josef KELLERMANN, Auteur ; Friedrich LOTTSPEICH, Auteur ; Sabine M. KLAUCK, Auteur ; Lore BREITENBACH-KOLLER, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress. Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways. The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects' and the ASD patients' set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress. Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mutation RPL10[H213Q] and LCLs from ASD patients without this mutation. At pathway levels, this redox-sensitive protein signature has also been identified in a yeast rpl10 deficiency and an oxidative stress model. These observations point to a common molecular pathomechanism in ASD, characterized in our study by dysregulation of redox balance. Importantly, this can be triggered by the known ASD-RPL10[H213Q] mutation or by yet unknown mutations of the ASD cohort that act upstream of RPL10 in differential expression of redox-sensitive proteins. En ligne : http://dx.doi.org/10.1186/2040-2392-5-10 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development / Ian ROSSMAN in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development Type de document : Texte imprimé et/ou numérique Auteurs : Ian ROSSMAN, Auteur ; Lulu LIN, Auteur ; Katherine MORGAN, Auteur ; Marissa DIGIOVINE, Auteur ; Elise VAN BUSKIRK, Auteur ; Silky KAMDAR, Auteur ; James MILLONIG, Auteur ; Emanuel DICICCO-BLOOM, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The homeobox transcription factor Engrailed2 (En2) has been studied extensively in neurodevelopment, particularly in the midbrain/hindbrain region and cerebellum, where it exhibits dynamic patterns of expression and regulates cell patterning and morphogenesis. Because of its roles in regulating cerebellar development and evidence of cerebellar pathology in autism spectrum disorder (ASD), we previously examined an ENGRAILED2 association and found evidence to support EN2 as a susceptibility gene, a finding replicated by several other investigators. However, its functions at the cell biological level remain undefined. In the mouse, En2 gene is expressed in granule neuron precursors (GNPs) just as they exit the cell cycle and begin to differentiate, raising the possibility that En2 may modulate these developmental processes. To define En2 functions, we examined proliferation, differentiation and signaling pathway activation in En2 knockout (KO) and wild-type (WT) GNPs in response to a variety of extracellular growth factors and following En2 cDNA overexpression in cell culture. In vivo analyses of cerebellar GNP proliferation as well as responses to insulin-like growth factor-1 (IGF1) treatment were also conducted. Proliferation markers were increased in KO GNPs in vivo and in 24-h cultures, suggesting En2 normally serves to promote cell cycle exit. Significantly, IGF1 stimulated greater DNA synthesis in KO than WT cells in culture, a finding associated with markedly increased phospho-S6 kinase activation. Similarly, there was three-fold greater DNA synthesis in the KO cerebellum in response to IGF1 in vivo. On the other hand, KO GNPs exhibited reduced neurite outgrowth and differentiation. Conversely, En2 overexpression increased cell cycle exit and promoted neuronal differentiation. In aggregate, our observations suggest that the ASD-associated gene En2 promotes GNP cell cycle exit and differentiation, and modulates IGF1 activity during postnatal cerebellar development. Thus, genetic/epigenetic alterations of EN2 expression may impact proliferation, differentiation and IGF1 signaling as possible mechanisms that may contribute to ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/2040-2392-5-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development [Texte imprimé et/ou numérique] / Ian ROSSMAN, Auteur ; Lulu LIN, Auteur ; Katherine MORGAN, Auteur ; Marissa DIGIOVINE, Auteur ; Elise VAN BUSKIRK, Auteur ; Silky KAMDAR, Auteur ; James MILLONIG, Auteur ; Emanuel DICICCO-BLOOM, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : The homeobox transcription factor Engrailed2 (En2) has been studied extensively in neurodevelopment, particularly in the midbrain/hindbrain region and cerebellum, where it exhibits dynamic patterns of expression and regulates cell patterning and morphogenesis. Because of its roles in regulating cerebellar development and evidence of cerebellar pathology in autism spectrum disorder (ASD), we previously examined an ENGRAILED2 association and found evidence to support EN2 as a susceptibility gene, a finding replicated by several other investigators. However, its functions at the cell biological level remain undefined. In the mouse, En2 gene is expressed in granule neuron precursors (GNPs) just as they exit the cell cycle and begin to differentiate, raising the possibility that En2 may modulate these developmental processes. To define En2 functions, we examined proliferation, differentiation and signaling pathway activation in En2 knockout (KO) and wild-type (WT) GNPs in response to a variety of extracellular growth factors and following En2 cDNA overexpression in cell culture. In vivo analyses of cerebellar GNP proliferation as well as responses to insulin-like growth factor-1 (IGF1) treatment were also conducted. Proliferation markers were increased in KO GNPs in vivo and in 24-h cultures, suggesting En2 normally serves to promote cell cycle exit. Significantly, IGF1 stimulated greater DNA synthesis in KO than WT cells in culture, a finding associated with markedly increased phospho-S6 kinase activation. Similarly, there was three-fold greater DNA synthesis in the KO cerebellum in response to IGF1 in vivo. On the other hand, KO GNPs exhibited reduced neurite outgrowth and differentiation. Conversely, En2 overexpression increased cell cycle exit and promoted neuronal differentiation. In aggregate, our observations suggest that the ASD-associated gene En2 promotes GNP cell cycle exit and differentiation, and modulates IGF1 activity during postnatal cerebellar development. Thus, genetic/epigenetic alterations of EN2 expression may impact proliferation, differentiation and IGF1 signaling as possible mechanisms that may contribute to ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/2040-2392-5-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Abnormal lateralization of functional connectivity between language and default mode regions in autism / Jared NIELSEN in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Abnormal lateralization of functional connectivity between language and default mode regions in autism Type de document : Texte imprimé et/ou numérique Auteurs : Jared NIELSEN, Auteur ; Brandon ZIELINSKI, Auteur ; P FLETCHER, Auteur ; Andrew A. ALEXANDER, Auteur ; Nicholas LANGE, Auteur ; Erin D. BIGLER, Auteur ; Janet E. LAINHART, Auteur ; Jeffrey S. ANDERSON, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Lateralization of brain structure and function occurs in typical development, and abnormal lateralization is present in various neuropsychiatric disorders. Autism is characterized by a lack of left lateralization in structure and function of regions involved in language, such as Broca and Wernicke areas. Using functional connectivity magnetic resonance imaging from a large publicly available sample (n=964), we tested whether abnormal functional lateralization in autism exists preferentially in language regions or in a more diffuse pattern across networks of lateralized brain regions. The autism group exhibited significantly reduced left lateralization in a few connections involving language regions and regions from the default mode network, but results were not significant throughout left- and right-lateralized networks. There is a trend that suggests the lack of left lateralization in a connection involving Wernicke area and the posterior cingulate cortex associates with more severe autism. Abnormal language lateralization in autism may be due to abnormal language development rather than to a deficit in hemispheric specialization of the entire brain. En ligne : http://dx.doi.org/10.1186/2040-2392-5-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Abnormal lateralization of functional connectivity between language and default mode regions in autism [Texte imprimé et/ou numérique] / Jared NIELSEN, Auteur ; Brandon ZIELINSKI, Auteur ; P FLETCHER, Auteur ; Andrew A. ALEXANDER, Auteur ; Nicholas LANGE, Auteur ; Erin D. BIGLER, Auteur ; Janet E. LAINHART, Auteur ; Jeffrey S. ANDERSON, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Lateralization of brain structure and function occurs in typical development, and abnormal lateralization is present in various neuropsychiatric disorders. Autism is characterized by a lack of left lateralization in structure and function of regions involved in language, such as Broca and Wernicke areas. Using functional connectivity magnetic resonance imaging from a large publicly available sample (n=964), we tested whether abnormal functional lateralization in autism exists preferentially in language regions or in a more diffuse pattern across networks of lateralized brain regions. The autism group exhibited significantly reduced left lateralization in a few connections involving language regions and regions from the default mode network, but results were not significant throughout left- and right-lateralized networks. There is a trend that suggests the lack of left lateralization in a connection involving Wernicke area and the posterior cingulate cortex associates with more severe autism. Abnormal language lateralization in autism may be due to abnormal language development rather than to a deficit in hemispheric specialization of the entire brain. En ligne : http://dx.doi.org/10.1186/2040-2392-5-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227