Nature Communications (Mar 2024)
Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
- 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,
- Thomas Arnesen,
- Henry Houlden
Affiliations
- Viorica Chelban
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Henriette Aksnes
- Department of Biomedicine, University of Bergen
- Reza Maroofian
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Lauren C. LaMonica
- Department of Cell Biology, Yale School of Medicine
- Luis Seabra
- Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163
- Anette Siggervåg
- Department of Biomedicine, University of Bergen
- Perrine Devic
- Hospices Civils de Lyon, Groupement Hospitalier Sud, Service d’Explorations Fonctionnelles Neurologiques
- Hanan E. Shamseldin
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Jana Vandrovcova
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- David Murphy
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology
- Anne-Claire Richard
- Univ Rouen Normandie, Inserm U1245, CHU Rouen, Department of Genetics and CNRMAJ
- Olivier Quenez
- Univ Rouen Normandie, Inserm U1245, CHU Rouen, Department of Genetics and CNRMAJ
- Antoine Bonnevalle
- Univ Rouen Normandie, Inserm U1245, CHU Rouen, Department of Genetics and CNRMAJ
- M. Natalia Zanetti
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology
- Rauan Kaiyrzhanov
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Vincenzo Salpietro
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Stephanie Efthymiou
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Lucia V. Schottlaender
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Heba Morsy
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Annarita Scardamaglia
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Ambreen Tariq
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- Alistair T. Pagnamenta
- Oxford NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics
- Ajia Pennavaria
- Department of Biomedicine, University of Bergen
- Liv S. Krogstad
- Department of Biomedicine, University of Bergen
- Åse K. Bekkelund
- Department of Biomedicine, University of Bergen
- Alessia Caiella
- Department of Biomedicine, University of Bergen
- Nina Glomnes
- Department of Biomedicine, University of Bergen
- Kirsten M. Brønstad
- Department of Biomedicine, University of Bergen
- Sandrine Tury
- Institut de Recherche en Infectiologie de Montpellier, Université de Montpellier, CNRS
- Andrés Moreno De Luca
- Department of Radiology, Autism & Developmental Medicine Institute, Geisinger
- Anne Boland-Auge
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)
- Robert Olaso
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)
- Jean-François Deleuze
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)
- Mathieu Anheim
- Neurology Department, Strasbourg University Hospital
- Benjamin Cretin
- Neurology Department, Strasbourg University Hospital
- Barbara Vona
- Institute of Human Genetics, University Medical Center Göttingen
- Fahad Alajlan
- Department of Neuroscience Center, King Faisal Specialist Hospital and Research Center
- Firdous Abdulwahab
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Jean-Luc Battini
- Institut de Recherche en Infectiologie de Montpellier, Université de Montpellier, CNRS
- Rojan İpek
- Paediatric Neurology, Faculty of Medicine, Dicle University
- Peter Bauer
- Centogene GmbH
- Giovanni Zifarelli
- Centogene GmbH
- Serdal Gungor
- Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Pediatrics, Division of Pediatric Neurology
- Semra Hiz Kurul
- Dokuz Eylul University, School of Medicine, Department of Paediatric Neurology
- Hanns Lochmuller
- Children’s Hospital of Eastern Ontario Research Institute and Division of Neurology, Department of Medicine, The Ottawa Hospital
- Sahar I. Da’as
- Department of Human Genetics, Sidra Medicine
- Khalid A. Fakhro
- Department of Human Genetics, Sidra Medicine
- Alicia Gómez-Pascual
- Department of Information and Communications Engineering, University of Murcia, Campus Espinardo
- Juan A. Botía
- Department of Information and Communications Engineering, University of Murcia, Campus Espinardo
- Nicholas W. Wood
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology
- Rita Horvath
- Department of Clinical Neurosciences, University of Cambridge
- Andreas M. Ernst
- Department of Cell Biology, Yale School of Medicine
- James E. Rothman
- Department of Cell Biology, Yale School of Medicine
- Meriel McEntagart
- Medical Genetics Department, St George’s University Hospitals
- Yanick J. Crow
- Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163
- Fowzan S. Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Gaël Nicolas
- Univ Rouen Normandie, Inserm U1245, CHU Rouen, Department of Genetics and CNRMAJ
- SYNaPS Study Group
- Thomas Arnesen
- Department of Biomedicine, University of Bergen
- Henry Houlden
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology
- DOI
- https://doi.org/10.1038/s41467-024-46354-0
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 20
Abstract
Abstract 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.
