Strain-dependent effects on neurobehavioral and seizure phenotypes in Scn2aK1422E mice.
Strain-dependent effects on neurobehavioral and seizure phenotypes in Scn2aK1422E mice.
复制标题
对 Scn2aK1422E 小鼠神经行为和癫痫表型的菌株依赖性影响。
DOI：
10.1101/2023.06.06.543929
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kearney,JenniferA
中科院分区：
文献类型：
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作者：
Echevarria-Cooper,DennisM;Hawkins,NicoleA;Kearney,JenniferA
SCN 2A中的致病性变体与一系列神经发育障碍（NDD）相关。尽管很大程度上是单基因的，但SCN 2A相关的NDD显示出相当大的表型变异和复杂的基因型-表型相关性。遗传修饰剂可导致与罕见驱动突变相关的疾病表型的变异性。因此，近交系啮齿动物品系之间的不同遗传背景已被证明会影响疾病相关的表型，包括与SCN 2A相关的NDD相关的表型。最近，我们开发了一种突变SCN 2A-p. K1422 E的小鼠模型，该模型作为C57 BL/6 J（B6）品系的等基因系维持。我们对杂合子Scn 2aK 1422 E小鼠NDD表型的初步表征揭示了焦虑相关行为和癫痫易感性的改变。为了确定背景品系是否影响Scn 2aK 1422 E小鼠模型中的表型严重程度，比较了B6和[DBA/2 J ×B6]F1杂交（F1 D2）品系小鼠的表型。来自神经行为测定的会聚证据表明，与野生型相比，Scn 2aK 1422 E小鼠的焦虑样行为较低，并进一步表明，与F1 D2背景相比，这种效应在B6背景下更明显。虽然罕见的自发性癫痫发作的发生没有应变依赖性差异，反应的化学惊厥剂红藻氨酸显示癫痫发作的泛化和致死性风险的差异，与应变和性别的基础上的变化。在Scn 2aK 1422 E小鼠模型中继续检查品系依赖性效应可以揭示具有独特易感性特征的遗传背景，这与未来特定性状的研究相关，并能够鉴定高度外显表型和修饰基因，这些基因可以为K1422 E变体的主要致病机制提供线索。
Pathogenic variants in SCN2A are associated with a range of neurodevelopmental disorders (NDD). Despite being largely monogenic, SCN2A-related NDD show considerable phenotypic variation and complex genotype-phenotype correlations. Genetic modifiers can contribute to variability in disease phenotypes associated with rare driver mutations. Accordingly, different genetic backgrounds across inbred rodent strains have been shown to influence disease-related phenotypes, including those associated with SCN2A-related NDD. Recently, we developed a mouse model of the variant SCN2A-p.K1422E that was maintained as an isogenic line on the C57BL/6J (B6) strain. Our initial characterization of NDD phenotypes in heterozygous Scn2aK1422E mice revealed alterations in anxiety-related behavior and seizure susceptibility. To determine if background strain affects phenotype severity in the Scn2aK1422E mouse model, phenotypes of mice on B6 and [DBA/2J×B6]F1 hybrid (F1D2) strains were compared. Convergent evidence from neurobehavioral assays demonstrated lower anxiety-like behavior in Scn2aK1422E mice compared to wild-type and further suggested that this effect is more pronounced on the B6 background compared to the F1D2 background. Although there were no strain-dependent differences in occurrence of rare spontaneous seizures, response to the chemoconvulsant kainic acid revealed differences in seizure generalization and lethality risk, with variation based on strain and sex. Continued examination of strain-dependent effects in the Scn2aK1422E mouse model could reveal genetic backgrounds with unique susceptibility profiles that would be relevant for future studies on specific traits and enable the identification of highly penetrant phenotypes and modifier genes that could provide clues about the primary pathogenic mechanism of the K1422E variant.