PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine–threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.

中文翻译：

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聚集在调节域的PPP3CA截短变异导致早发难治性癫痫

PPP3CA编码钙调磷酸酶的催化​​亚基，钙调磷酸酶是一种钙-钙调蛋白调节的丝氨酸-苏氨酸磷酸酶。催化结构域中的功能丧失（LoF）变异与癫痫有关，而自抑制结构域中的功能获得（GoF）变异会导致多种先天性异常。我们在此报告了五名患有 de novo PPP3CA变异的新患者。有趣的是，本研究中的两个移码变体和之前报道的六个截短变体都位于调节域（RD）的26个氨基酸区域内。与 LoF 错义变异患者相比，截短变异患者的癫痫发作更早，而自闭症谱系障碍是后者更常见的特征。截短变体的表达研究表明，突变等位基因有明显的 RNA 表达，但没有检测到突变蛋白。我们的数据表明，PPP3CA截短变体聚集在 RD 中，导致更严重的早发难治性癫痫，并代表一种不同于 LoF 或 GoF 错义变体的变体类型。