Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries

Wan, Lily; Du, Liqing; Xiao, Wenbiao; Zhang, Bo-Xin; Yan, Xiao‐Xin; Luo, Zhaohui; Xiao, Bo

doi:10.1007/s10571-021-01054-x

Cited by 10 publications

(11 citation statements)

References 133 publications

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“…In addition, SHANK1 was under-expressed in the cerebral cortex of MIA offspring from LPS-challenged rats that presented neuroinflammation and cortical synaptic deficit [67]. SHANK1 mRNA is expressed predominately in the cerebral cortex, hippocampus, and amygdala and an isoform survey included SHANK1B (lacking the C-terminal SAM domain), SHANK1C (lacking the N-terminal ankyrin repeat domain), and SHANK1D (lacking the ankyrin repeat domain, and SH3 or SAM domains) [68]. The most extreme MEGF8 isoform was under-expressed (8.7%) in MIA relative to control weaned females, and this finding could be correlated with reports of gene variants associated with SSD [69].…”

Section: Differential Alternative Splicing Associated With Maternal I...mentioning

confidence: 99%

Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

Southey

Keever-Keigher

Rymut

et al. 2021

Immuno

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The inflammatory response of gestating females to infection or stress can disrupt gene expression in the offspring’s amygdala, resulting in lasting neurodevelopmental, physiological, and behavioral disorders. The effects of maternal immune activation (MIA) can be impacted by the offspring’s sex and exposure to additional stressors later in life. The objectives of this study were to investigate the disruption of alternative splicing patterns associated with MIA in the offspring’s amygdala and characterize this disruption in the context of the second stress of weaning and sex. Differential alternative splicing was tested on the RNA-seq profiles of a pig model of viral-induced MIA. Compared to controls, MIA was associated with the differential alternative splicing (FDR-adjusted p-value < 0.1) of 292 and 240 genes in weaned females and males, respectively, whereas 132 and 176 genes were differentially spliced in control nursed female and male, respectively. The majority of the differentially spliced (FDR-adjusted p-value < 0.001) genes (e.g., SHANK1, ZNF672, KCNA6) and many associated enriched pathways (e.g., Fc gamma R-mediated phagocytosis, non-alcoholic fatty liver disease, and cGMP-PKG signaling) have been reported in MIA-related disorders including autism and schizophrenia in humans. Differential alternative splicing associated with MIA was detected in the gene MAG across all sex-stress groups except for unstressed males and SLC2A11 across all groups except unstressed females. Precise understanding of the effect of MIA across second stressors and sexes necessitates the consideration of splicing isoform profiles.

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Section: Differential Alternative Splicing Associated With Maternal I...mentioning

confidence: 99%

Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

Southey

Keever-Keigher

Rymut

et al. 2021

Immuno

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“…As briefly noted in the Introduction, SHANK3 alterations are risk factors for several neuropsychiatric diseases. Various lines of genetically modified mice and, more recently, rats and macaques have been generated to understand the underlying pathogenic cellular, molecular, and neurocircuitry mechanisms ( Bozdagi et al, 2010 ; Peça et al, 2011 ; Wang et al, 2011 ; Kouser et al, 2013 ; Lee et al, 2015 ; Jaramillo et al, 2016 ; Wang et al, 2016 , 2017 ; Copping et al, 2017 ; Dhamne et al, 2017 ; Vicidomini et al, 2017 ; Drapeau et al, 2018 ; Kabitzke et al, 2018 ; Yoo et al, 2018 ; Guo et al, 2019 ; Zhou et al, 2019 ; Wan et al, 2021 ). These animal models display many neurobehavioral phenotypes ruminant to human symptoms in neuropsychiatric disorders, such as repetitive/compulsive behavior, abnormal social communication and interaction, impaired learning and memory, reduced locomotion activity, and increased anxiety-like behavior.…”

Section: Discussionmentioning

confidence: 99%

“…SHANK3 gene is located on chromosome 22q13.3 in humans, spans ∼55.1 kb in length, and contains 24 exons, six alternative promoters, and one alternative stop codon located in the exon 21b. Besides alternative promoter and mRNA splicing, the gene expression is regulated by epigenetic mechanisms, resulting in tissue specific localization of its mRNA and protein ( Wan et al, 2021 ). Previous studies in rodents have shown that Shank3 mRNA expression appears to be high in the brain, heart, and spleen ( Lim et al, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer’s Disease

Wan

Ai²,

Yang³

et al. 2021

Front. Aging Neurosci.

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Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer’s disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.

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“…Since SHANK3 mutations have been associated with neuropsychiatric disorders more prevalent than PMS [56,57] it is fortunate that the role of pharmacogenetic considerations in treatment has been described in detail [58][59][60]. For instance, patients prescribed the anticonvulsant carbamazepine who test positive for variants of the HLA-A or HLA-B genes (specifically HLA-A*31:01 or HLA-B*15:02) are at risk for serious adverse reactions [61].…”

Section: Pharmacogenomics In Pms With Particular Focus On Cyp2d6 Located At 22q132mentioning

confidence: 99%

Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome

Dyar

Meaddough

Sarasua

et al. 2021

Genes

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Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from < 50kb to > 9Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS.

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Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries

Cited by 10 publications

References 133 publications

Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer’s Disease

Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome

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