Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications.
Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications.
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DOI：
10.1186/s11689-021-09397-8
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发表时间：
2021-11-16
影响因子：
4.9
通讯作者：
Boeckers TM
中科院分区：
文献类型：
--
作者：
Delling JP;Boeckers TM
自闭症谱系障碍(ASD)是一种神经发育疾病，具有临床异质性和高遗传性的特点。ASD的核心症状包括社交沟通和互动方面的缺陷，以及受限的、重复的行为、兴趣或活动模式。已经发现了许多与ASD风险增加相关的基因。这些ASD危险基因编码的蛋白质通常参与与胎儿大脑发育、染色质修饰和基因表达调控有关的过程，以及突触的结构和功能完整性。SH3和多个Ankyrin重复结构域(Shank)家族的基因编码兴奋性突触和其他大分子复合体的关键支架蛋白(SHANK1-3)。Shank基因突变与ASD密切相关，更具体地说，是由于22q13.3杂合性缺失导致SHANK3单倍体功能不全或SHANK3错义变异引起的Phelan-Mcdermid综合征(PMDS)。SHANK3缺乏症和潜在的治疗方案已经在动物模型中进行了广泛的研究，特别是在小鼠身上，也在大鼠和非人类灵长类动物中进行了研究。然而，目前所提出的治疗策略还很少转化为临床实践。本文综述了有关SHANK3基因缺陷动物模型的文献。特别是，结构、行为和神经异常的描述和比较，提供了一个广泛和全面的概述。此外，还讨论了潜在的病理生理学机制以及在这些模型中研究的可能的治疗方法，并就其对ASD或PMDS相关表型的影响进行了评估。由各种遗传策略产生的SHANK3缺乏症动物模型，决定了残留SHANK3亚型的组成和受影响的细胞类型，表现出类似ASD和PMDS的表型。多个模型和研究的表型异质性与人类ASD和PMDS患者临床严重程度的变化相似。已经提出了多种治疗策略，并在动物模型中进行了测试，这可能会导致对患有ASD和/或PMDS的人类患者的翻译影响。未来的研究应该探索针对遗传单倍体不足的新治疗方法的效果，如CRISPR介导的启动子激活。
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. 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. 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.
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影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
6.2
作者：
Bozdagi O;Tavassoli T;Buxbaum JD
通讯作者：
Buxbaum JD
DOI：
10.1002/aur.1925
发表时间：
2018-04
期刊：
Autism research : official journal of the International Society for Autism Research
影响因子：
--
作者：
Berg EL;Copping NA;Rivera JK;Pride MC;Careaga M;Bauman MD;Berman RF;Lein PJ;Harony-Nicolas H;Buxbaum JD;Ellegood J;Lerch JP;Wöhr M;Silverman JL
通讯作者：
Silverman JL
影响因子：
4.7
作者：
Boeckers, TM;Liedtke, T;Gundelfinger, ED
通讯作者：
Gundelfinger, ED
影响因子：
5.2
作者：
Boccuto, Luigi;Lauri, Maria;Schwartz, Charles E.
通讯作者：
Schwartz, Charles E.