Nature communications · 2024

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, SYNaPS Study Group, Arnesen Thomas, Houlden Henry

Аннотация

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.

Предметные рубрики MeSH

Humans Acetylation Brain Brain Diseases Inheritance Patterns Mutation Phosphates Sodium-Phosphate Cotransporter Proteins, Type III N-Terminal Acetyltransferase F

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

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Аннотация

Предметные рубрики MeSH