Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interes...

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Autores principales:	Jan Philipp Delling, Tobias M. Boeckers
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	SHANK3 Autism spectrum disorder ASD Phelan-McDermid syndrome PMDS Therapy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/ae6654901b7240b0acc5734c1d080d86
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spelling	oai:doaj.org-article:ae6654901b7240b0acc5734c1d080d862021-11-21T12:03:14ZComparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications10.1186/s11689-021-09397-81866-19471866-1955https://doaj.org/article/ae6654901b7240b0acc5734c1d080d862021-11-01T00:00:00Zhttps://doi.org/10.1186/s11689-021-09397-8https://doaj.org/toc/1866-1947https://doaj.org/toc/1866-1955Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.Jan Philipp DellingTobias M. BoeckersBMCarticleSHANK3Autism spectrum disorderASDPhelan-McDermid syndromePMDSTherapyNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENJournal of Neurodevelopmental Disorders, Vol 13, Iss 1, Pp 1-37 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SHANK3 Autism spectrum disorder ASD Phelan-McDermid syndrome PMDS Therapy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	SHANK3 Autism spectrum disorder ASD Phelan-McDermid syndrome PMDS Therapy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Jan Philipp Delling Tobias M. Boeckers Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
description	Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.
format	article
author	Jan Philipp Delling Tobias M. Boeckers
author_facet	Jan Philipp Delling Tobias M. Boeckers
author_sort	Jan Philipp Delling
title	Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
title_short	Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
title_full	Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
title_fullStr	Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
title_full_unstemmed	Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
title_sort	comparison of shank3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
publisher	BMC
publishDate	2021
url	https://doaj.org/article/ae6654901b7240b0acc5734c1d080d86
work_keys_str_mv	AT janphilippdelling comparisonofshank3deficiencyinanimalmodelsphenotypestreatmentstrategiesandtranslationalimplications AT tobiasmboeckers comparisonofshank3deficiencyinanimalmodelsphenotypestreatmentstrategiesandtranslationalimplications
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Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

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