Neurodevelopmental disorders, including intellectual disability and autism spectrum disorder, are often caused by de novo autosomal dominant mutations. While mouse models are frequently used to investigate these disorders, the genetic background sometimes affects the appearance or severity of mutant phenotypes. In a previous report, we developed a system to produce de novo heterozygous mutant mice using the Cre-LoxP system without the need to maintain the heterozygous mutant line itself (Takagi et al. 2015). To further verify the applicability of the de novo mutation system in sperm, we used this system to produce a mouse model for Rubinstein-Taybi syndrome, using a Cbp heterozygous mutant, which has been reported to be difficult to maintain on a C57BL/6 background. Here, we show that de novo Cbp- loss-of-function heterozygous mutant mice with a C57BL/6 background, present with a clear craniofacial phenotype and reduced locomotor activity in the open field test, which was not observed in the loss-of-function of Cbp heterozygous mutant line mice with a mixed genetic background, but was observed in the dominant negative Cbp heterozygous mutant line with a mixed genetic background. Meanwhile, the de novo heterozygous Cbp mutant mice still showed great variability in survival rates despite their inbred background. These results further confirmed that the de novo mutation system used in germ cells is effective for stable production and analysis of an autosomal dominant disorder mouse model, which is often difficult to maintain as a mutant mouse line.

神经发育障碍，包括智力残疾和自闭症谱系障碍，通常是由引起从头常染色体显性遗传突变。虽然小鼠模型经常用于研究这些疾病，但遗传背景有时会影响突变表型的外观或严重程度。在之前的一份报告中，我们开发了一个系统来使用 Cre-LoxP 系统生产从头杂合突变小鼠，而无需维持杂合突变系本身（Takagi 等人，2015 年）。为了进一步验证从头突变系统在精子中的适用性，我们使用该系统生成了 Rubinstein-Taybi 综合征的小鼠模型，使用了Cbp杂合突变体，据报道难以在 C57BL/6 背景下维持。在这里，我们展示了具有 C57BL/6 背景的de novo Cbp - 功能丧失杂合突变小鼠，在开放场测试中表现出清晰的颅面表型和降低的运动活动，这在损失的 -具有混合遗传背景的Cbp杂合突变系小鼠的功能，但在具有混合遗传背景的显性负Cbp杂合突变系中观察到。同时，尽管具有近交背景，从头杂合Cbp突变小鼠的存活率仍然显示出很大的变异性。这些结果进一步证实了de novo 生殖细胞中使用的突变系统对于常染色体显性遗传疾病小鼠模型的稳定生产和分析是有效的，该模型通常难以作为突变小鼠品系维持。