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.
- 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.
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.
- Department of Neurosurgery, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany..
- Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy; Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy.
- Clinical Pediatric Genetic Unit, Pediatric Clinic, Fondazione MBBM, San Gerardo Hospital, Monza 20900, Italy.
- ErasmusMC University Medical Center, Department of Clinical Genetics, Rotterdam 3015, the Netherlands.
- Leiden University Medical Center, Clinical Genetics, Leiden 2333, the Netherlands.
- Praxis für Humangenetik-Friedrichstrasse, Berlin 10117, Germany.
- Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany; CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen 72076, Germany.
- Department of Neuropediatrics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany.
- Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA.
- Division of Genetic and Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA.
- Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht 6229, the Netherlands.
- Severinus Institute for Intellectual Disability, 5507 Veldhoven, the Netherlands.
- Division of Biochemical Genetics, Department of Pediatrics, University of British Columbia, BC Children’s Hospital, Vancouver, BC V6H 3N1, Canada.
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525, the Netherlands.
- Service de Pathologie Centre Hospitalier Universitaire de Bordeaux, Bordeaux 33000, France; MRGM, Maladies Rares: Génétique et Métabolisme, INSERM U1211, Université de Bordeaux, Bordeaux 33076, France.
- Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux 33076, France.
- The Genetics Institute, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.
- Service de Génértique, CHBA, Vannes 56000, France.
- Institute for Clinical Genetics, Bonn 53111, Germany.
- Pediatric Genetics, East Tennessee Children’s Hospital, Knoxville, TN 37916, USA.
- Clinical Genomics Program, GeneDx, Inc., Gaithersburg, MD 20877, USA.
- Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany. Electronic address: email@example.com.