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