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

Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism / David M. JAMES in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 3 p. Titre : Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism Type de document : texte imprimé Auteurs : David M. JAMES, Auteur ; Robert A. KOZOL, Auteur ; Yuji KAJIWARA, Auteur ; Adam L. WAHL, Auteur ; Emily C. STORRS, Auteur ; Joseph D. BUXBAUM, Auteur ; Mason KLEIN, Auteur ; Baharak MOSHIREE, Auteur ; Julia E. DALLMAN, Auteur Article en page(s) : 3 p. Langues : Anglais (eng) Mots-clés : *Digestive transit  *Enteroendocrine  *Peristaltic rate  *Phelan-McDermid syndrome  approved by the Institutional Animal Care and Use Committee of University of  Miami.The authors declare that they have no competing interests.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background and aims: Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods: To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abDeltaC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abDeltaC (+/-) heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results: Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abDeltaC (+/-) mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abDeltaC (+/-) mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abDeltaC (+/-) and shank3abDeltaC (-/-) mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abDeltaC (+/-) larvae. Conclusions: Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0250-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism [texte imprimé] / David M. JAMES, Auteur ; Robert A. KOZOL, Auteur ; Yuji KAJIWARA, Auteur ; Adam L. WAHL, Auteur ; Emily C. STORRS, Auteur ; Joseph D. BUXBAUM, Auteur ; Mason KLEIN, Auteur ; Baharak MOSHIREE, Auteur ; Julia E. DALLMAN, Auteur . - 3 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 3 p. Mots-clés : *Digestive transit  *Enteroendocrine  *Peristaltic rate  *Phelan-McDermid syndrome  approved by the Institutional Animal Care and Use Committee of University of  Miami.The authors declare that they have no competing interests.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background and aims: Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods: To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abDeltaC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abDeltaC (+/-) heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results: Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abDeltaC (+/-) mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abDeltaC (+/-) mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abDeltaC (+/-) and shank3abDeltaC (-/-) mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abDeltaC (+/-) larvae. Conclusions: Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0250-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

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