De novo variants in ATP2B1 lead to neurodevelopmental delay.

5. Mai 2022

Rahimi MJ1, Urban N2, Wegler M1, Sticht H3, Schaefer M2, Popp B1, Gaunitz F4, Morleo M5, Nigro V5, Maitz S6, Mancini GMS7, Ruivenkamp C8, Suk EK9, Bartolomaeus T10, Merkenschlager A11, Koboldt D12, Bartholomew D13, Stegmann APA14, Sinnema M14, Duynisveld I15, Salvarinova R16, Race S16, de Vries BBA17, Trimouille A18, Naudion S19, Marom D20, Hamiel U20, Henig N20, Demurger F21, Rahner N22, Bartels E22, Hamm JA23, Putnam AM23, Person R24, Jamra RA 1, Oppermann H25


Calcium (Ca2+) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca2+ pumps that participate in the regulation of intracellular free Ca2+. 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 Ca2+ imaging after introducing all nine missense variants in transfected HEK293 cells and showed that all variants lead to a significant decrease in Ca2+ 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.

Keywords: ATP2B1; abnormal behavior; calcium homeostasis; de novo; development delay; intellectual disability; neurodevelopmental disorder; seizure.