Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism-Relevant Behaviors in Mice.
Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism-Relevant Behaviors in Mice.
复制标题
DOI：
10.1371/journal.pone.0146366
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Brindle PK
中科院分区：
文献类型：
--
作者：
Zheng F;Kasper LH;Bedford DC;Lerach S;Teubner BJ;Brindle PK
自闭症谱系障碍（ASD）是一组神经发育障碍，其特征是重复行为，社会互动缺陷和沟通技能受损。对于大多数ASD患者来说，根本原因是未知的。在大约25%的ASD病例中发现了基因突变，包括表观遗传调节因子的突变，这表明染色质或DNA功能失调是ASD的关键组成部分。组蛋白乙酰转移酶CREB结合蛋白（CBP，CREBBP）的突变导致Rubinstein-Taybi综合征（RTS），这是一种包括ASD样症状的发育障碍。最近，涉及大量ASD患者家族的基因组研究在理论上将CBP及其parabolic p300（EP 300）建模为ASD相关蛋白和基因相互作用网络中的关键枢纽，并在CBP乙酰转移酶和CH 1结构域的高度保守残基中鉴定了从头错义突变。在这里，我们提供了动物模型的证据，支持CBP及其CH 1结构域与自闭症相关的观点。我们发现，CBP CH 1（TAZ 1）结构域缺失突变（CBPΔ CH 1/Δ CH 1）的小鼠具有RTS样表型，包括ASD相关的重复行为、多动、社会互动缺陷、运动功能障碍、识别记忆受损和突触可塑性异常。因此，我们的研究结果表明，CBP CH 1结构域功能的丧失有助于RTS，并可能导致ASD，并且该结构域在正常的运动功能，认知和社会行为中起着重要作用。尽管ASD相关表观遗传调节因子突变影响的关键生理功能一直是个谜，但我们的研究结果与ASD中涉及CBP和p300的理论模型一致，并且与最近描述的ASD相关CBP突变的致病作用一致。
Autism spectrum disorders (ASDs) are a group of neurodevelopmental afflictions characterized by repetitive behaviors, deficits in social interaction, and impaired communication skills. For most ASD patients, the underlying causes are unknown. Genetic mutations have been identified in about 25 percent of ASD cases, including mutations in epigenetic regulators, suggesting that dysregulated chromatin or DNA function is a critical component of ASD. Mutations in the histone acetyltransferase CREB binding protein (CBP, CREBBP) cause Rubinstein-Taybi Syndrome (RTS), a developmental disorder that includes ASD-like symptoms. Recently, genomic studies involving large numbers of ASD patient families have theoretically modeled CBP and its paralog p300 (EP300) as critical hubs in ASD-associated protein and gene interaction networks, and have identified de novo missense mutations in highly conserved residues of the CBP acetyltransferase and CH1 domains. Here we provide animal model evidence that supports this notion that CBP and its CH1 domain are relevant to autism. We show that mice with a deletion mutation in the CBP CH1 (TAZ1) domain (CBPΔCH1/ΔCH1) have an RTS-like phenotype that includes ASD-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity. Our results therefore indicate that loss of CBP CH1 domain function contributes to RTS, and possibly ASD, and that this domain plays an essential role in normal motor function, cognition and social behavior. Although the key physiological functions affected by ASD-associated mutation of epigenetic regulators have been enigmatic, our findings are consistent with theoretical models involving CBP and p300 in ASD, and with a causative role for recently described ASD-associated CBP mutations.