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Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications

journal contribution
submitted on 2024-08-11, 05:10 and posted on 2024-08-11, 05:10 authored by Viorica Chelban, Henriette Aksnes, Reza Maroofian, Lauren C. LaMonica, Luis Seabra, Anette Siggervåg, Perrine Devic, Hanan E. Shamseldin, Jana Vandrovcova, David Murphy, Anne-Claire Richard, Olivier Quenez, Antoine Bonnevalle, M. Natalia Zanetti, Rauan Kaiyrzhanov, Vincenzo Salpietro, Stephanie Efthymiou, Lucia V. Schottlaender, Heba Morsy, Annarita Scardamaglia, Ambreen Tariq, Alistair T. Pagnamenta, Ajia Pennavaria, Liv S. Krogstad, Åse K. Bekkelund, Alessia Caiella, Nina Glomnes, Kirsten M. Brønstad, Sandrine Tury, Andrés Moreno De Luca, Anne Boland-Auge, Robert Olaso, Jean-François Deleuze, Mathieu Anheim, Benjamin Cretin, Barbara Vona, Fahad Alajlan, Firdous Abdulwahab, Jean-Luc Battini, Rojan İpek, Peter Bauer, Giovanni Zifarelli, Serdal Gungor, Semra Hiz Kurul, Hanns Lochmuller, Sahar I. Da’as, Khalid A. Fakhro, Alicia Gómez-Pascual, Juan A. Botía, Nicholas W. Wood, Rita Horvath, Andreas M. Ernst, James E. Rothman, Meriel McEntagart, Yanick J. Crow, Fowzan S. Alkuraya, Gaël Nicolas, SYNaPS Study Group, Henry Houlden, Thomas Arnesen

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

Other Information

Published in: Nature Communications
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: https://dx.doi.org/10.1038/s41467-024-46354-0

History

Language

  • English

Publisher

Springer Nature

Publication Year

  • 2024

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Sidra Medicine
  • Clinical Research Centre - Sidra Medicine
  • Weill Cornell Medicine - Qatar

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