Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are highly heterogeneous in clinical symptoms as well as etiologies. Mutations in SHANK2 are associated with ASD and accordingly, Shank2 knockout mouse shows ASD-like behavioral phenotypes, including social deficits. Intriguingly, two lines of Shank2 knockout (KO) mouse generated by deleting different exons (exon 6-7 or exon 7) showed distinct cellular phenotypes. Previously, we compared gene expressions between Shank2 KOs lacking exon 6-7 (e6-7 KO) and KOs lacking exon 7 (e7 KO) by performing RNA-seq. In this study, we expanded transcriptomic analyses to identify novel transcriptional variants in the KO mice. We found prominent expression of a novel exon (exon 4' or e4') between the existing exons 4 and 5 in the Shank2 e6-7 KO model. Expression of the transcriptional variant harboring this novel exon was confirmed by RT-PCR and western blotting. These findings suggest that the novel variant may function as a modifier gene, which contributes to the differences between the two Shank2 mutant lines. Furthermore, our result further represents an example of genetic compensation that may lead to phenotypic heterogeneity among ASD patients with mutations in the same gene.

中文翻译：

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在自闭症谱系障碍的Shank2基因敲除小鼠模型中鉴定新型Shank2转录变异体。

自闭症谱系障碍（ASD）是一组神经发育障碍，在临床症状和病因上高度异质。SHANK2中的突变与ASD相关，因此Shank2基因敲除小鼠显示出ASD样的行为表型，包括社交缺陷。有趣的是，通过删除不同的外显子（外显子6-7或外显子7）生成的两行Shank2基因敲除（KO）小鼠表现出不同的细胞表型。以前，我们通过执行RNA序列比较了缺少外显子6-7的Shank2 KO（e6-7 KO）和缺少外显子7的KOs（e7 KO）的基因表达。在这项研究中，我们扩展了转录组学分析，以鉴定KO小鼠中的新型转录变异体。我们在Shank2 e6-7 KO模型的现有外显子4和5之间发现了新型外显子（外显子4'或e4'）的突出表达。通过RT-PCR和western印迹证实了具有该新的外显子的转录变体的表达。这些发现表明，新的变体可以充当修饰基因，其导致两个Shank2突变体系之间的差异。此外，我们的结果进一步代表了遗传补偿的一个例子，该遗传补偿可能导致具有相同基因突变的ASD患者出现表型异质性。