A Frank Assessment of SHANK: Impacts of Pathogenic Variations in SHANK3 on Preclinical Models of Phelan McDermid Syndrome / Vic LIN in Autism Research, 18-10 (October 2025)  

Public ISBD [article]  inAutism Research > 18-10 (October 2025) . - p.1935-1964 Titre : A Frank Assessment of SHANK: Impacts of Pathogenic Variations in SHANK3 on Preclinical Models of Phelan McDermid Syndrome Type de document : texte imprimé Auteurs : Vic LIN, Auteur ; Samantha M. MATTA, Auteur ; Julia E. DALLMAN, Auteur ; Suzanne HOSIE, Auteur ; Manon MOREAU, Auteur ; Ashley E. FRANKS, Auteur ; Thomas BOURGERON, Auteur ; Elisa L. HILL-YARDIN, Auteur Article en page(s) : p.1935-1964 Langues : Anglais (eng) Mots-clés : autism  behavior  brain  gut  mouse  Phelan McDermid  SHANK3 Index. décimale : PER Périodiques Résumé : ABSTRACT Although there are as many as 40 preclinical models of the neurodevelopmental disorder Phelan McDermid syndrome (PMS, or 22q13.3 deletion syndrome), detailed phenotypic analyses to compare the effects of different pathogenic variants and inform treatment design are lacking. Here, we clarify behavioral traits (social, vocalization, repetitive and anxiety-like behavior), developmental trajectories, and motor activity in addition to changes in brain structure and function in 10 widely available Shank3 transgenic mouse models. Although behavioral deficits in Shank3B?/? and Shank3?C/?C mice were most extensively reported, each model reviewed here displayed autism-relevant behavioral traits. Most studies focused on assessing social, anxiety-like, and repetitive behavior, whereas few studies examined changes in vocalization, developmental milestones, motor function, or aggressive behavior. We did not identify any studies of gut function in the ten selected Shank3 models. Alterations in the gastrointestinal microbiome of Shank3-deficient mice are associated with changes in bacterial abundance and composition, which may impact social behavior and gastrointestinal function. Studying preclinical models can provide critical insights into molecular pathways contributing to PMS. Further research is needed to determine how various genetic variations in Shank3 impact the brain, behavior, and potentially the gastrointestinal system. En ligne : https://doi.org/10.1002/aur.70112 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=569 [article] A Frank Assessment of SHANK: Impacts of Pathogenic Variations in SHANK3 on Preclinical Models of Phelan McDermid Syndrome [texte imprimé] / Vic LIN, Auteur ; Samantha M. MATTA, Auteur ; Julia E. DALLMAN, Auteur ; Suzanne HOSIE, Auteur ; Manon MOREAU, Auteur ; Ashley E. FRANKS, Auteur ; Thomas BOURGERON, Auteur ; Elisa L. HILL-YARDIN, Auteur . - p.1935-1964. Langues : Anglais (eng) in Autism Research > 18-10 (October 2025) . - p.1935-1964 Mots-clés : autism  behavior  brain  gut  mouse  Phelan McDermid  SHANK3 Index. décimale : PER Périodiques Résumé : ABSTRACT Although there are as many as 40 preclinical models of the neurodevelopmental disorder Phelan McDermid syndrome (PMS, or 22q13.3 deletion syndrome), detailed phenotypic analyses to compare the effects of different pathogenic variants and inform treatment design are lacking. Here, we clarify behavioral traits (social, vocalization, repetitive and anxiety-like behavior), developmental trajectories, and motor activity in addition to changes in brain structure and function in 10 widely available Shank3 transgenic mouse models. Although behavioral deficits in Shank3B?/? and Shank3?C/?C mice were most extensively reported, each model reviewed here displayed autism-relevant behavioral traits. Most studies focused on assessing social, anxiety-like, and repetitive behavior, whereas few studies examined changes in vocalization, developmental milestones, motor function, or aggressive behavior. We did not identify any studies of gut function in the ten selected Shank3 models. Alterations in the gastrointestinal microbiome of Shank3-deficient mice are associated with changes in bacterial abundance and composition, which may impact social behavior and gastrointestinal function. Studying preclinical models can provide critical insights into molecular pathways contributing to PMS. Further research is needed to determine how various genetic variations in Shank3 impact the brain, behavior, and potentially the gastrointestinal system. En ligne : https://doi.org/10.1002/aur.70112 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=569

Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 / Suzanne HOSIE in Autism Research, 12-7 (July 2019)  

Public ISBD [article]  inAutism Research > 12-7 (July 2019) . - p.1043-1056 Titre : Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 Type de document : texte imprimé Auteurs : Suzanne HOSIE, Auteur ; Melina ELLIS, Auteur ; Mathusi SWAMINATHAN, Auteur ; Fatima RAMALHOSA, Auteur ; Gracia O. SEGER, Auteur ; Gayathri K. BALASURIYA, Auteur ; Christopher GILLBERG, Auteur ; Maria RASTAM, Auteur ; Leonid CHURILOV, Auteur ; Sonja J. MCKEOWN, Auteur ; Nalzi YALCINKAYA, Auteur ; Petri URVIL, Auteur ; Tor SAVIDGE, Auteur ; Carolyn A. BELL, Auteur ; Oonagh BODIN, Auteur ; Jen WOOD, Auteur ; Ashley E. FRANKS, Auteur ; Joel C. BORNSTEIN, Auteur ; Elisa L. HILL-YARDIN, Auteur Année de publication : 2019 Article en page(s) : p.1043-1056 Langues : Anglais (eng) Mots-clés : autism  gastrointestinal symptoms  gut motility  immunofluorescence  mouse  neuroligin-3 Index. décimale : PER Périodiques Résumé : Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3(R451C) ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3(R451C) compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3(R451C) mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3(R451C) mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3(R451C) mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3(R451C) mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication. En ligne : http://dx.doi.org/10.1002/aur.2127 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402 [article] Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 [texte imprimé] / Suzanne HOSIE, Auteur ; Melina ELLIS, Auteur ; Mathusi SWAMINATHAN, Auteur ; Fatima RAMALHOSA, Auteur ; Gracia O. SEGER, Auteur ; Gayathri K. BALASURIYA, Auteur ; Christopher GILLBERG, Auteur ; Maria RASTAM, Auteur ; Leonid CHURILOV, Auteur ; Sonja J. MCKEOWN, Auteur ; Nalzi YALCINKAYA, Auteur ; Petri URVIL, Auteur ; Tor SAVIDGE, Auteur ; Carolyn A. BELL, Auteur ; Oonagh BODIN, Auteur ; Jen WOOD, Auteur ; Ashley E. FRANKS, Auteur ; Joel C. BORNSTEIN, Auteur ; Elisa L. HILL-YARDIN, Auteur . - 2019 . - p.1043-1056. Langues : Anglais (eng) in Autism Research > 12-7 (July 2019) . - p.1043-1056 Mots-clés : autism  gastrointestinal symptoms  gut motility  immunofluorescence  mouse  neuroligin-3 Index. décimale : PER Périodiques Résumé : Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3(R451C) ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3(R451C) compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3(R451C) mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3(R451C) mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3(R451C) mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3(R451C) mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication. En ligne : http://dx.doi.org/10.1002/aur.2127 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402

A preliminary study of pharmacogenetic biomarkers for individuals with autism and gastrointestinal dysfunction / A.E. SHINDLER in Research in Autism Spectrum Disorders, 71 (March 2020)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 71 (March 2020) . - p.101516 Titre : A preliminary study of pharmacogenetic biomarkers for individuals with autism and gastrointestinal dysfunction Type de document : texte imprimé Auteurs : A.E. SHINDLER, Auteur ; Elisa L. HILL-YARDIN, Auteur ; S. PETROVSKI, Auteur ; N. BISHOP, Auteur ; Ashley E. FRANKS, Auteur Article en page(s) : p.101516 Langues : Anglais (eng) Mots-clés : ASD  Gastrointestinal dysfunction  Pharmacogenetics  Antidepressants  Antipsychotics Index. décimale : PER Périodiques Résumé : Background Autism Spectrum Disorder (ASD) symptoms are commonly treated with a variety of pharmaceuticals which can have adverse side effects. A study of pharmacogenetic biomarkers for ASD medications and association with gastrointestinal (GI) dysfunction symptoms was conducted in individuals diagnosed with autism and/or GI dysfunction to provide further information on the genetic risk in relation to treatment effectiveness. Methods A total of sixty participants were recruited, 10 with autism and GI dysfunction, 21 with GI dysfunction (without autism) and 29 without autism or GI dysfunction (typical controls). Buccal cell samples were collected and sequenced. A GI dysfunction questionnaire which included questions regarding prescription of medications associated with treating ASD symptoms was provided to the participants. To calculate Odds Ratios and compare the average of risk allele expression frequency of the SNPS being investigated, the sequencing and questionnaire data were analyzed using the epiR package and Welch Two Sample T-tests, respectively, using the R statistics program. The Bonferroni correction was utilized to correct for multiple comparisions. Results People in the autism group were more likely to express the risk alleles for the Cytochrome P450 family 2 subfamily C member 9 rs1057910 and Solute Carrier family 6, member 2 rs3785143 SNPs; however, after the Bonferroni correction these findings were not statistically significant (CYP2C9 rs1057910, P = 0.074; SLC6A2, rs3785143, P = 0.4218). Conclusions Further research is warranted to reveal the potential use of CYP2C9 and SLC6A2 SNP expression as pharmacogenetic biomarkers to determine the most appropriate medication for individuals with autism and/or GI dysfunction. En ligne : https://doi.org/10.1016/j.rasd.2020.101516 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=417 [article] A preliminary study of pharmacogenetic biomarkers for individuals with autism and gastrointestinal dysfunction [texte imprimé] / A.E. SHINDLER, Auteur ; Elisa L. HILL-YARDIN, Auteur ; S. PETROVSKI, Auteur ; N. BISHOP, Auteur ; Ashley E. FRANKS, Auteur . - p.101516. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 71 (March 2020) . - p.101516 Mots-clés : ASD  Gastrointestinal dysfunction  Pharmacogenetics  Antidepressants  Antipsychotics Index. décimale : PER Périodiques Résumé : Background Autism Spectrum Disorder (ASD) symptoms are commonly treated with a variety of pharmaceuticals which can have adverse side effects. A study of pharmacogenetic biomarkers for ASD medications and association with gastrointestinal (GI) dysfunction symptoms was conducted in individuals diagnosed with autism and/or GI dysfunction to provide further information on the genetic risk in relation to treatment effectiveness. Methods A total of sixty participants were recruited, 10 with autism and GI dysfunction, 21 with GI dysfunction (without autism) and 29 without autism or GI dysfunction (typical controls). Buccal cell samples were collected and sequenced. A GI dysfunction questionnaire which included questions regarding prescription of medications associated with treating ASD symptoms was provided to the participants. To calculate Odds Ratios and compare the average of risk allele expression frequency of the SNPS being investigated, the sequencing and questionnaire data were analyzed using the epiR package and Welch Two Sample T-tests, respectively, using the R statistics program. The Bonferroni correction was utilized to correct for multiple comparisions. Results People in the autism group were more likely to express the risk alleles for the Cytochrome P450 family 2 subfamily C member 9 rs1057910 and Solute Carrier family 6, member 2 rs3785143 SNPs; however, after the Bonferroni correction these findings were not statistically significant (CYP2C9 rs1057910, P = 0.074; SLC6A2, rs3785143, P = 0.4218). Conclusions Further research is warranted to reveal the potential use of CYP2C9 and SLC6A2 SNP expression as pharmacogenetic biomarkers to determine the most appropriate medication for individuals with autism and/or GI dysfunction. En ligne : https://doi.org/10.1016/j.rasd.2020.101516 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=417

Towards Identifying Genetic Biomarkers for Gastrointestinal Dysfunction in Autism / A.E. SHINDLER in Journal of Autism and Developmental Disorders, 50-1 (January 2020)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 50-1 (January 2020) . - p.76-86 Titre : Towards Identifying Genetic Biomarkers for Gastrointestinal Dysfunction in Autism Type de document : texte imprimé Auteurs : A.E. SHINDLER, Auteur ; Elisa L. HILL-YARDIN, Auteur ; S. PETROVSKI, Auteur ; N. BISHOP, Auteur ; Ashley E. FRANKS, Auteur Article en page(s) : p.76-86 Langues : Anglais (eng) Mots-clés : Autism  Constipation  Diarrhea  Gastrointestinal dysfunction  Nausea  Single nucleotide polymorphism Index. décimale : PER Périodiques Résumé : This study investigated genetic biomarkers for gastrointestinal dysfunction symptoms in order to provide further information on the genetic risk for GI dysfunction associated with autism. The single nucleotide polymorphisms of sixty participants with autism and/or gastrointestinal dysfunction were analyzed. The autism group had a moderate statistical significance for the Prolactin (PRL) (OR 6.35, p value 0.069) and Interleukin 10 (IL-10) (OR 0.25, p value 0.087) SNPs. The GI dysfunction group had a strong statistical significance for the Cluster of Differentiation 38 (CD38) (OR 6.88, p value 0.005) and oxytocin receptor (OXTR) (OR 0.27, p value 0.036) SNPs. The potential use of PRL, IL-10, CD38, and OXTR SNP expression as biomarkers for GI dysfunction in autism warrants further research. En ligne : http://dx.doi.org/10.1007/s10803-019-04231-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] Towards Identifying Genetic Biomarkers for Gastrointestinal Dysfunction in Autism [texte imprimé] / A.E. SHINDLER, Auteur ; Elisa L. HILL-YARDIN, Auteur ; S. PETROVSKI, Auteur ; N. BISHOP, Auteur ; Ashley E. FRANKS, Auteur . - p.76-86. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 50-1 (January 2020) . - p.76-86 Mots-clés : Autism  Constipation  Diarrhea  Gastrointestinal dysfunction  Nausea  Single nucleotide polymorphism Index. décimale : PER Périodiques Résumé : This study investigated genetic biomarkers for gastrointestinal dysfunction symptoms in order to provide further information on the genetic risk for GI dysfunction associated with autism. The single nucleotide polymorphisms of sixty participants with autism and/or gastrointestinal dysfunction were analyzed. The autism group had a moderate statistical significance for the Prolactin (PRL) (OR 6.35, p value 0.069) and Interleukin 10 (IL-10) (OR 0.25, p value 0.087) SNPs. The GI dysfunction group had a strong statistical significance for the Cluster of Differentiation 38 (CD38) (OR 6.88, p value 0.005) and oxytocin receptor (OXTR) (OR 0.27, p value 0.036) SNPs. The potential use of PRL, IL-10, CD38, and OXTR SNP expression as biomarkers for GI dysfunction in autism warrants further research. En ligne : http://dx.doi.org/10.1007/s10803-019-04231-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

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