Neurobehavioral characteristics of mice with SETD5 mutations as models of IDD23 and KBG syndromes.
Neurobehavioral characteristics of mice with SETD5 mutations as models of IDD23 and KBG syndromes.
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DOI：
10.3389/fgene.2022.1022339
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发表时间：
2022
影响因子：
3.7
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中科院分区：
文献类型：
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基因组分析表明，许多患有神经发育障碍（NDD）的个体中各种染色质调节因子的基因发生突变，强调了染色质调节在神经系统发育和功能中的重要作用。染色质调节由组蛋白和DNA修饰的写入器、读取器和擦除器介导，这些蛋白质由特定结构域定义。这些结构域之一是SET结构域，其存在于催化组蛋白甲基化的酶中。在患有NDD（IDD 23）（智力发育障碍，常染色体显性遗传23）的个体中，已鉴定出SETD 5（含SET结构域5）基因的杂合功能丧失突变。KBG综合征（以该病症的前三个家族的姓氏首字母命名）的特征与IDD 23的特征重叠或不同，最初认为仅由ANKRD 11（含11的锚蛋白重复结构域）基因突变引起。然而，最近的研究已经在一些没有ANKRD 11突变的KBG综合征患者中发现了SETD 5突变。在这里，我们总结了四个独立的研究小组进行的Setd 5 +/−小鼠的神经行为特征，比较IDD 23和KBG表型，并解决了小鼠模型的实用性和未来的发展，以阐明NDD发病机制的基础上，重点是SETD 5及其相关蛋白。
Genomic analysis has revealed that the genes for various chromatin regulators are mutated in many individuals with neurodevelopmental disorders (NDDs), emphasizing the important role of chromatin regulation in nervous system development and function. Chromatin regulation is mediated by writers, readers, and erasers of histone and DNA modifications, with such proteins being defined by specific domains. One of these domains is the SET domain, which is present in enzymes that catalyze histone methylation. Heterozygous loss-of-function mutations of the SETD5 (SET domain containing 5) gene have been identified in individuals with an NDD designated IDD23 (intellectual developmental disorder, autosomal dominant 23). KBG syndrome (named after the initials of the last names of the first three families identified with the condition) is characterized by features that either overlap with or are distinct from those of IDD23 and was initially thought to be caused only by mutations in the ANKRD11 (ankyrin repeat domain containing 11) gene. However, recent studies have identified SETD5 mutations in some KBG syndrome patients without ANKRD11 mutations. Here we summarize the neurobehavioral characterization of Setd5 +/− mice performed by four independent research groups, compare IDD23 and KBG phenotypes, and address the utility and future development of mouse models for elucidation of the mechanisms underlying NDD pathogenesis, with a focus on SETD5 and its related proteins.