De novo variants in ATP2B1 lead to neurodevelopmental delay

Rahimi MJ, Urban N, Wegler M, Sticht H, Schaefer M, Popp B, Gaunitz F, Morleo M, Nigro V, Maitz S, Mancini GM, Ruivenkamp C, Suk EK, Bartolomaeus T, Merkenschlager A, Koboldt D, Bartholomew D, Stegmann AP, Sinnema M, Duynisveld I, Salvarinova R, Race S, de Vries BB, Trimouille A, Naudion S, Marom D, Hamiel U, Henig N, Demurger F, Rahner N, Bartels E, Hamm JA, Putnam AM, Person R, Abou Jamra R, Oppermann H (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 109

Pages Range: 944-952

Journal Issue: 5

DOI: 10.1016/j.ajhg.2022.03.009

Abstract

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.

Authors with CRIS profile

Involved external institutions

Telethon Institute of Genetics and Medicine (TIGEM) Italy (IT) Azienda Ospedaliera San Gerardo (ASST Monza) Italy (IT) Maastricht University Netherlands (NL) Severinus Netherlands (NL) University of British Columbia Canada (CA) Donders Institute for Brain, Cognition and Behaviour Netherlands (NL) Centre Hospitalier Universitaire de Bordeaux / CHU Bordeaux France (FR) East Tennessee Children's Hospital (ETCH) United States (USA) (US) Universität Leipzig Germany (DE) Erasmus University Medical Center (MC) Netherlands (NL) Leiden University Medical Center Netherlands (NL) Nationwide Children's Hospital United States (USA) (US) Tel Aviv University Israel (IL) Centre hospitalier Bretagne Atlantique (CHBA) France (FR) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) GeneDX United States (USA) (US)

How to cite

APA:

Rahimi, M.J., Urban, N., Wegler, M., Sticht, H., Schaefer, M., Popp, B.,... Oppermann, H. (2022). De novo variants in ATP2B1 lead to neurodevelopmental delay. American Journal of Human Genetics, 109(5), 944-952. https://doi.org/10.1016/j.ajhg.2022.03.009

MLA:

Rahimi, Meer Jacob, et al. "De novo variants in ATP2B1 lead to neurodevelopmental delay." American Journal of Human Genetics 109.5 (2022): 944-952.

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