Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 / Susan E. MALONEY in Autism Research, 11-1 (January 2018)  

Public ISBD [article]  inAutism Research > 11-1 (January 2018) . - p.44-58 Titre : Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 Type de document : Texte imprimé et/ou numérique Auteurs : Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.44-58 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss?of?function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal?separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole?brain serotonin was observed in Nf1+/– mice, but whole?brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD?relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)?relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333 [article] Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 [Texte imprimé et/ou numérique] / Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.44-58. Langues : Anglais (eng) in Autism Research > 11-1 (January 2018) . - p.44-58 Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss?of?function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal?separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole?brain serotonin was observed in Nf1+/– mice, but whole?brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD?relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)?relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333

Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association / Han YUAN in Autism Research, 7-2 (April 2014)  

Public ISBD [article]  inAutism Research > 7-2 (April 2014) . - p.245-253 Titre : Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association Type de document : Texte imprimé et/ou numérique Auteurs : Han YUAN, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.245-253 Mots-clés : maternal genotype effect  autism  GWAS  AGRE  SSC Index. décimale : PER Périodiques Résumé : Like most psychiatric disorders, autism spectrum disorders have both a genetic and an environmental component. While previous studies have clearly demonstrated the contribution of in utero (prenatal) environment on autism risk, most of them focused on transient environmental factors. Based on a recent sibling study, we hypothesized that environmental factors could also come from the maternal genome, which would result in persistent effects across siblings. In this study, the possibility of maternal genotype effects was examined by looking for common variants (single-nucleotide polymorphisms or SNPs) in the maternal genome associated with increased risk of autism in children. A case/control genome-wide association study was performed using mothers of probands as cases, and either fathers of probands or normal females as controls. Autism Genetic Resource Exchange and Illumina Genotype Control Database were used as our discovery cohort (n?=?1616). The same analysis was then replicated on Simon Simplex Collection and Study of Addiction: Genetics and Environment datasets (n?=?2732). We did not identify any SNP that reached genome-wide significance (P??10?8), and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles of effective size marginally below our power to detect. En ligne : http://dx.doi.org/10.1002/aur.1363 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230 [article] Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association [Texte imprimé et/ou numérique] / Han YUAN, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.245-253. in Autism Research > 7-2 (April 2014) . - p.245-253 Mots-clés : maternal genotype effect  autism  GWAS  AGRE  SSC Index. décimale : PER Périodiques Résumé : Like most psychiatric disorders, autism spectrum disorders have both a genetic and an environmental component. While previous studies have clearly demonstrated the contribution of in utero (prenatal) environment on autism risk, most of them focused on transient environmental factors. Based on a recent sibling study, we hypothesized that environmental factors could also come from the maternal genome, which would result in persistent effects across siblings. In this study, the possibility of maternal genotype effects was examined by looking for common variants (single-nucleotide polymorphisms or SNPs) in the maternal genome associated with increased risk of autism in children. A case/control genome-wide association study was performed using mothers of probands as cases, and either fathers of probands or normal females as controls. Autism Genetic Resource Exchange and Illumina Genotype Control Database were used as our discovery cohort (n?=?1616). The same analysis was then replicated on Simon Simplex Collection and Study of Addiction: Genetics and Environment datasets (n?=?2732). We did not identify any SNP that reached genome-wide significance (P??10?8), and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles of effective size marginally below our power to detect. En ligne : http://dx.doi.org/10.1002/aur.1363 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus / Jake GOCKLEY in Molecular Autism, (May 2015)  

Public ISBD [article]  inMolecular Autism > (May 2015) . - p.1-10 Titre : The female protective effect in autism spectrum disorder is not mediated by a single genetic locus Type de document : Texte imprimé et/ou numérique Auteurs : Jake GOCKLEY, Auteur ; A. Jeremy WILLSEY, Auteur ; Shan DONG, Auteur ; Joseph D. DOUGHERTY, Auteur ; John N. CONSTANTINO, Auteur ; Stephan J. SANDERS, Auteur Article en page(s) : p.1-10 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. En ligne : http://dx.doi.org/10.1186/s13229-015-0014-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] The female protective effect in autism spectrum disorder is not mediated by a single genetic locus [Texte imprimé et/ou numérique] / Jake GOCKLEY, Auteur ; A. Jeremy WILLSEY, Auteur ; Shan DONG, Auteur ; Joseph D. DOUGHERTY, Auteur ; John N. CONSTANTINO, Auteur ; Stephan J. SANDERS, Auteur . - p.1-10. Langues : Anglais (eng) in Molecular Autism > (May 2015) . - p.1-10 Index. décimale : PER Périodiques Résumé : A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. En ligne : http://dx.doi.org/10.1186/s13229-015-0014-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

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