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Article Dans Une Revue American Journal of Human Genetics Année : 2022

De novo variants in ATP2B1 lead to neurodevelopmental delay.

Irma Duynisveld
  • Fonction : Auteur
Sophie Naudion
  • Fonction : Auteur
Daphna Marom
  • Fonction : Auteur
Uri Hamiel
  • Fonction : Auteur
Noa Henig
  • Fonction : Auteur
Nils Rahner
  • Fonction : Auteur
Enrika Bartels
  • Fonction : Auteur
J Austin Hamm
  • Fonction : Auteur
Abbey M Putnam
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-04152067 , version 1 (05-07-2023)

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Meer Jacob Rahimi, Nicole Urban, Meret Wegler, Heinrich Sticht, Michael Schaefer, et al.. De novo variants in ATP2B1 lead to neurodevelopmental delay.. American Journal of Human Genetics, 2022, 109 (5), pp.944-952. ⟨10.1016/j.ajhg.2022.03.009⟩. ⟨hal-04152067⟩
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