TY - JOUR
T1 - De novo variants in ATP2B1 lead to neurodevelopmental delay
AU - Rahimi, Meer Jacob
AU - Urban, Nicole
AU - Wegler, Meret
AU - Sticht, Heinrich
AU - Schaefer, Michael
AU - Popp, Bernt
AU - Gaunitz, Frank
AU - Morleo, Manuela
AU - Nigro, Vincenzo
AU - Maitz, Silvia
AU - Mancini, Grazia M S
AU - Ruivenkamp, Claudia
AU - Suk, Eun-Kyung
AU - Bartolomaeus, Tobias
AU - Merkenschlager, Andreas
AU - Koboldt, Daniel
AU - Bartholomew, Dennis
AU - Stegmann, Alexander P A
AU - Sinnema, Margje
AU - Duynisveld, Irma
AU - Salvarinova, Ramona
AU - Race, Simone
AU - de Vries, Bert B A
AU - Trimouille, Aurélien
AU - Naudion, Sophie
AU - Marom, Daphna
AU - Hamiel, Uri
AU - Henig, Noa
AU - Demurger, Florence
AU - Rahner, Nils
AU - Bartels, Enrika
AU - Hamm, J Austin
AU - Putnam, Abbey M
AU - Person, Richard
AU - Abou Jamra, Rami
AU - Oppermann, Henry
N1 - Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2022/5/5
Y1 - 2022/5/5
N2 - 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.
AB - 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.
KW - BINDING
KW - CA2+
KW - EXPRESSION
KW - HOMEOSTASIS
KW - HOUSEKEEPING FUNCTION
KW - INTELLECTUAL DISABILITY
KW - ISOFORMS
KW - MUTATION
KW - PLASMA-MEMBRANE CA2+-ATPASE
U2 - 10.1016/j.ajhg.2022.03.009
DO - 10.1016/j.ajhg.2022.03.009
M3 - Article
C2 - 35358416
VL - 109
SP - 944
EP - 952
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -