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

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

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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