3 recherche sur le mot-clé 'Exons'

Behavioral decline in Shank3(?ex4-22) mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes / James O BEAVERS ; Romana HYDE ; Roseline EWA ; Amber SCHWERTMAN ; Sarahi PORCAYO ; Ben D. RICHARDSON in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 52 Titre : Behavioral decline in Shank3(?ex4-22) mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes Type de document : texte imprimé Auteurs : James O BEAVERS, Auteur ; Romana HYDE, Auteur ; Roseline EWA, Auteur ; Amber SCHWERTMAN, Auteur ; Sarahi PORCAYO, Auteur ; Ben D. RICHARDSON, Auteur Article en page(s) : 52 Langues : Anglais (eng) Mots-clés : Animals  *Nerve Tissue Proteins/metabolism/genetics  *Mice, Knockout  *Synapses/metabolism  Male  *Behavior, Animal  Mice  *Excitatory Postsynaptic Potentials  Female  *Cerebellum/metabolism  Microfilament Proteins/metabolism/genetics  Glutamic Acid/metabolism  Exons  Mice, Inbred C57BL  Neurons/metabolism  Ampar  Autism spectrum disorder  Cerebellum  Glutamate receptor  Granule cell  Mouse behavior  Phelan-McDermid syndrome  Shank3  accordance with protocols approved by the Institutional Animal Care and Use  Committee at Southern Illinois Universe - School of Medicine or the University of  Idaho. Consent for publication: Not applicable. Competing interests: The authors  declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although Shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in Shank3(?ex4-22) mice at two developmental stages. METHODS: Shank3(?ex4-22) wildtype, heterozygous, and homozygous knockout mice lacking exons 4-22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5-7 weeks old) and adult (3-5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of Shank3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology. RESULTS: Deletion of Shank3 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult Shank3(?ex4-22) knockout male mice, while self-grooming was uniquely elevated in males across both age groups. Heterozygous mice showed little to no changes in behavioral phenotypes in most behavioral tests. Immunofluorescence staining indicated the presence of Shank3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identified a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs. LIMITATIONS: Other behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how Shank3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum and whether these changes shape the behavioral phenotype. CONCLUSIONS: Our findings reveal an age-related exacerbation of behavioral impairments in Shank3(?ex4-22) mutant mice. These results suggest that Shank3 may alter the function of glutamatergic receptors at the mossy fiber-cerebellar granule cell synapse as a potential mechanism causing cerebellar disruption in ASD. En ligne : https://dx.doi.org/10.1186/s13229-024-00628-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Behavioral decline in Shank3(?ex4-22) mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes [texte imprimé] / James O BEAVERS, Auteur ; Romana HYDE, Auteur ; Roseline EWA, Auteur ; Amber SCHWERTMAN, Auteur ; Sarahi PORCAYO, Auteur ; Ben D. RICHARDSON, Auteur . - 52. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 52 Mots-clés : Animals  *Nerve Tissue Proteins/metabolism/genetics  *Mice, Knockout  *Synapses/metabolism  Male  *Behavior, Animal  Mice  *Excitatory Postsynaptic Potentials  Female  *Cerebellum/metabolism  Microfilament Proteins/metabolism/genetics  Glutamic Acid/metabolism  Exons  Mice, Inbred C57BL  Neurons/metabolism  Ampar  Autism spectrum disorder  Cerebellum  Glutamate receptor  Granule cell  Mouse behavior  Phelan-McDermid syndrome  Shank3  accordance with protocols approved by the Institutional Animal Care and Use  Committee at Southern Illinois Universe - School of Medicine or the University of  Idaho. Consent for publication: Not applicable. Competing interests: The authors  declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although Shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in Shank3(?ex4-22) mice at two developmental stages. METHODS: Shank3(?ex4-22) wildtype, heterozygous, and homozygous knockout mice lacking exons 4-22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5-7 weeks old) and adult (3-5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of Shank3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology. RESULTS: Deletion of Shank3 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult Shank3(?ex4-22) knockout male mice, while self-grooming was uniquely elevated in males across both age groups. Heterozygous mice showed little to no changes in behavioral phenotypes in most behavioral tests. Immunofluorescence staining indicated the presence of Shank3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identified a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs. LIMITATIONS: Other behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how Shank3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum and whether these changes shape the behavioral phenotype. CONCLUSIONS: Our findings reveal an age-related exacerbation of behavioral impairments in Shank3(?ex4-22) mutant mice. These results suggest that Shank3 may alter the function of glutamatergic receptors at the mossy fiber-cerebellar granule cell synapse as a potential mechanism causing cerebellar disruption in ASD. En ligne : https://dx.doi.org/10.1186/s13229-024-00628-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia / Kanako ISHIZUKA in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia Type de document : texte imprimé Auteurs : Kanako ISHIZUKA, Auteur ; Tomoyuki YOSHIDA, Auteur ; Takeshi KAWABATA, Auteur ; Ayako IMAI, Auteur ; Hisashi MORI, Auteur ; Hiroki KIMURA, Auteur ; Toshiya INADA, Auteur ; Yuko OKAHISA, Auteur ; Jun EGAWA, Auteur ; Masahide USAMI, Auteur ; Itaru KUSHIMA, Auteur ; Mako MORIKAWA, Auteur ; Takashi OKADA, Auteur ; Masashi IKEDA, Auteur ; Aleksic BRANKO, Auteur ; Daisuke MORI, Auteur ; Toshiyuki SOMEYA, Auteur ; Nakao IWATA, Auteur ; Norio OZAKI, Auteur Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics  Calcium-Binding Proteins/genetics  Exons  Heterozygote  Humans  Mutation  Neural Cell Adhesion Molecules/genetics  Schizophrenia/genetics  Autism spectrum disorders  Genotype-phenotype  Missense variants  Nrxn1  Neurodevelopmental disorder  Schizophrenia  Targeted resequencing  Ultra-rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ. METHODS: To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling. RESULTS: Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal. CONCLUSIONS: The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ. En ligne : https://dx.doi.org/10.1186/s11689-020-09325-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia [texte imprimé] / Kanako ISHIZUKA, Auteur ; Tomoyuki YOSHIDA, Auteur ; Takeshi KAWABATA, Auteur ; Ayako IMAI, Auteur ; Hisashi MORI, Auteur ; Hiroki KIMURA, Auteur ; Toshiya INADA, Auteur ; Yuko OKAHISA, Auteur ; Jun EGAWA, Auteur ; Masahide USAMI, Auteur ; Itaru KUSHIMA, Auteur ; Mako MORIKAWA, Auteur ; Takashi OKADA, Auteur ; Masashi IKEDA, Auteur ; Aleksic BRANKO, Auteur ; Daisuke MORI, Auteur ; Toshiyuki SOMEYA, Auteur ; Nakao IWATA, Auteur ; Norio OZAKI, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Autism Spectrum Disorder/genetics  Calcium-Binding Proteins/genetics  Exons  Heterozygote  Humans  Mutation  Neural Cell Adhesion Molecules/genetics  Schizophrenia/genetics  Autism spectrum disorders  Genotype-phenotype  Missense variants  Nrxn1  Neurodevelopmental disorder  Schizophrenia  Targeted resequencing  Ultra-rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ. METHODS: To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling. RESULTS: Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal. CONCLUSIONS: The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ. En ligne : https://dx.doi.org/10.1186/s11689-020-09325-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder / Chia-Lin YIN in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 23p. Titre : Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder Type de document : texte imprimé Auteurs : Chia-Lin YIN, Auteur ; Hsin-I CHEN, Auteur ; Ling-Hui LI, Auteur ; Yi-Ling CHIEN, Auteur ; Hsiao-Mei LIAO, Auteur ; Miao-Churn CHOU, Auteur ; Wen-Jiun CHOU, Auteur ; Wen-Che TSAI, Auteur ; Yen-Nan CHIU, Auteur ; Yu-Yu WU, Auteur ; Chen-Zen LO, Auteur ; Jer-Yuarn WU, Auteur ; Yen-Tsz CHEN, Auteur ; Susan Shur-Fen GAU, Auteur Article en page(s) : 23p. Langues : Anglais (eng) Mots-clés : Adolescent  Asian Continental Ancestry Group/genetics  Autism Spectrum Disorder/etiology/genetics  Child  China  Cohort Studies  DNA Copy Number Variations  Down-Regulation  Exons  Female  Genome-Wide Association Study  Genotype  Humans  Male  Odds Ratio  Pedigree  Phenotype  Polymorphism, Single Nucleotide  Ubiquitin-Protein Ligases/genetics  Autism spectrum disorder (ASD)  Copy number variations (CNVs)  Family study  Gene expression  Park2 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population. METHODS: To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR). RESULTS: A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2-4 of the PARK2 gene. CONCLUSIONS: Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494754. En ligne : http://dx.doi.org/10.1186/s13229-016-0087-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder [texte imprimé] / Chia-Lin YIN, Auteur ; Hsin-I CHEN, Auteur ; Ling-Hui LI, Auteur ; Yi-Ling CHIEN, Auteur ; Hsiao-Mei LIAO, Auteur ; Miao-Churn CHOU, Auteur ; Wen-Jiun CHOU, Auteur ; Wen-Che TSAI, Auteur ; Yen-Nan CHIU, Auteur ; Yu-Yu WU, Auteur ; Chen-Zen LO, Auteur ; Jer-Yuarn WU, Auteur ; Yen-Tsz CHEN, Auteur ; Susan Shur-Fen GAU, Auteur . - 23p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 23p. Mots-clés : Adolescent  Asian Continental Ancestry Group/genetics  Autism Spectrum Disorder/etiology/genetics  Child  China  Cohort Studies  DNA Copy Number Variations  Down-Regulation  Exons  Female  Genome-Wide Association Study  Genotype  Humans  Male  Odds Ratio  Pedigree  Phenotype  Polymorphism, Single Nucleotide  Ubiquitin-Protein Ligases/genetics  Autism spectrum disorder (ASD)  Copy number variations (CNVs)  Family study  Gene expression  Park2 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population. METHODS: To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR). RESULTS: A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2-4 of the PARK2 gene. CONCLUSIONS: Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494754. En ligne : http://dx.doi.org/10.1186/s13229-016-0087-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329