Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany.
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig Hospitals and Clinics, Leipzig 04107, Germany.
Am J Hum Genet. 2022 May 5;109(5):944-952. doi: 10.1016/j.ajhg.2022.03.009. Epub 2022 Mar 30.
Calcium (Ca) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca pumps that participate in the regulation of intracellular free Ca. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism, seizures, and distal limb abnormalities. Nine probands harbor missense variants, seven of which were in specific functional domains, and three individuals have nonsense variants. 3D structural protein modeling suggested that the variants have a destabilizing effect on the protein. We performed Ca imaging after introducing all nine missense variants in transfected HEK293 cells and showed that all variants lead to a significant decrease in Ca export capacity compared with the wild-type construct, thus proving their pathogenicity. Furthermore, we observed for the same variant set an incorrect intracellular localization of ATP2B1. The genetic findings and the overlapping phenotype of the probands as well as the functional analyses imply that de novo variants in ATP2B1 lead to a monogenic form of neurodevelopmental disorder.
钙（Ca）是一种普遍的第二信使，参与突触发生和细胞存活；因此，其调节对神经元很重要。ATP 酶质膜 Ca 转运 1（ATP2B1）属于 ATP 驱动的钙调蛋白依赖性 Ca 泵家族，参与细胞内游离 Ca 的调节。在这里，我们临床描述了一组 12 名无关联个体的 ATP2B1 变异和重叠表型的轻度至中度全球发育迟缓。其他常见症状包括自闭症、癫痫发作和远端肢体异常。9 名先证者携带错义变异，其中 7 种位于特定功能域，3 名个体携带无义变异。3D 结构蛋白建模表明，这些变异对蛋白质有不稳定作用。我们在转染的 HEK293 细胞中引入所有 9 种错义变异后进行了 Ca 成像，并表明所有变异与野生型构建体相比导致 Ca 外排能力显著降低，从而证明了它们的致病性。此外，我们观察到相同的变异集存在 ATP2B1 的细胞内定位错误。遗传发现和先证者的重叠表型以及功能分析表明，ATP2B1 中的新生变异导致一种单基因形式的神经发育障碍。
