Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Chelban V. Aksnes H. Maroofian R. LaMonica L.C. Seabra L. Siggervåg A. Devic P. Shamseldin H.E. Vandrovcova J. Murphy D. Richard A.-C. Quenez O. Bonnevalle A. Zanetti M.N. Kaiyrzhanov R. Salpietro V. Efthymiou S. Schottlaender L.V. Morsy H. Scardamaglia A. Tariq A. Pagnamenta A.T. Pennavaria A. Krogstad L.S. Bekkelund Å.K. Caiella A. Glomnes N. Brønstad K.M. Tury S. Moreno De Luca A. Boland-Auge A. Olaso R. Deleuze J.-F. Anheim M. Cretin B. Vona B. Alajlan F. Abdulwahab F. Battini J.-L. İpek R. Bauer P. Zifarelli G. Gungor S. Kurul S.H. Lochmuller H. Da’as S.I. Fakhro K.A. Gómez-Pascual A. Botía J.A. Wood N.W. Horvath R. Ernst A.M. Rothman J.E. McEntagart M. Crow Y.J. Alkuraya F.S. Nicolas G. Houlden H. Arnesen T.
December 2024Nature Research
Nature Communications
2024#15Issue 1
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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Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
Neurobiology and Medical Genetics Laboratory, “Nicolae Testemitanu” State University of Medicine and Pharmacy, 165, Stefan cel Mare si Sfant Boulevard, MD, Chisinau, 2004, Moldova
Department of Biomedicine, University of Bergen, Bergen, Norway
Department of Cell Biology, Yale School of Medicine, New Haven, CT, United States
Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Paris, France
Hospices Civils de Lyon, Groupement Hospitalier Sud, Service d’Explorations Fonctionnelles Neurologiques, Lyon, France
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
Univ Rouen Normandie, Inserm U1245, CHU Rouen, Department of Genetics and CNRMAJ, Rouen, F-76000, France
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
South Kazakhstan Medical Academy Shymkent, Shymkent, 160019, Kazakhstan
Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan Domingo Perón 1500, Pilar, B1629AHJ, Argentina
Instituto de medicina genómica (IMeG), Hospital Universitario Austral, Universidad Austral, Av. Juan Domingo Perón 1500, Pilar, B1629AHJ, Argentina
Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
Oxford NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, Oxford, United Kingdom
Department of Clinical Science, University of Bergen, Bergen, 5020, Norway
Institut de Recherche en Infectiologie de Montpellier, Université de Montpellier, CNRS, Montpellier, France
Department of Radiology, Autism & amp; Developmental Medicine Institute, Geisinger, Lewisburg, PA, United States
Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen’s University Faculty of Health Sciences, Kingston, ON, Canada
Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, 91057, France
Neurology Department, Strasbourg University Hospital, Strasbourg, France
Strasbourg Federation of Translational Medicine (FMTS), Strasbourg University, Strasbourg, France
INSERM-U964; CNRS-UMR7104, University of Strasbourg, Illkirch-Graffenstaden, France
Institute of Human Genetics, University Medical Center Göttingen, Göttingen, 37073, Germany
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, 37075, Germany
Department of Neuroscience Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Paediatric Neurology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
Centogene GmbH, Am Strande 7, Rostock, 18055, Germany
Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Pediatrics, Division of Pediatric Neurology, Malatya, Turkey
Dokuz Eylul University, School of Medicine, Department of Paediatric Neurology, Izmir, Turkey
Children’s Hospital of Eastern Ontario Research Institute and Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada
Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
Department of Neuropediatrics and Muscle Disorders, Medical Center–University of Freiburg, Faculty of Medicine, Freiburg, Germany
Department of Human Genetics, Sidra Medicine, Doha, Qatar
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
Weill Cornell Medical College, Doha, Qatar
Department of Information and Communications Engineering, University of Murcia, Campus Espinardo, Murcia, 30100, Spain
Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, United Kingdom
Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
School of Biological Sciences, Department of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, United States
Medical Genetics Department, St George’s University Hospitals, London, SWI7 0RE, United Kingdom
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
Department of Surgery, Haukeland University Hospital, Bergen, Norway
King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Department of Neuromuscular Diseases
Neurobiology and Medical Genetics Laboratory
Department of Biomedicine
Department of Cell Biology
Université Paris Cité
Hospices Civils de Lyon
Department of Translational Genomics
Department of Clinical and Movement Neurosciences
Univ Rouen Normandie
Department of Clinical and Experimental Epilepsy
South Kazakhstan Medical Academy Shymkent
Instituto de Investigaciones en Medicina Traslacional (IIMT)
Instituto de medicina genómica (IMeG)
Department of Human Genetics
Oxford NIHR Biomedical Research Centre
Department of Clinical Science
Institut de Recherche en Infectiologie de Montpellier
Department of Radiology
Department of Radiology
Université Paris-Saclay
Neurology Department
Strasbourg Federation of Translational Medicine (FMTS)
INSERM-U964; CNRS-UMR7104
Institute of Human Genetics
Institute for Auditory Neuroscience and InnerEarLab
Department of Neuroscience Center
Paediatric Neurology
Centogene GmbH
Inonu University
Dokuz Eylul University
Children’s Hospital of Eastern Ontario Research Institute and Division of Neurology
Brain and Mind Research Institute
Department of Neuropediatrics and Muscle Disorders
Department of Human Genetics
College of Health and Life Sciences
Weill Cornell Medical College
Department of Information and Communications Engineering
Neurogenetics Laboratory
Department of Clinical Neurosciences
School of Biological Sciences
Medical Genetics Department
MRC Human Genetics Unit
Department of Anatomy and Cell Biology
Department of Surgery
King Faisal Specialist Hospital and Research Center
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