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

Author

Listed:
  • Viorica Chelban

    (UCL Queen Square Institute of Neurology
    “Nicolae Testemitanu” State University of Medicine and Pharmacy)

  • Henriette Aksnes

    (University of Bergen)

  • Reza Maroofian

    (UCL Queen Square Institute of Neurology)

  • Lauren C. LaMonica

    (Yale School of Medicine)

  • Luis Seabra

    (INSERM UMR 1163)

  • Anette Siggervåg

    (University of Bergen)

  • Perrine Devic

    (Service d’Explorations Fonctionnelles Neurologiques)

  • Hanan E. Shamseldin

    (King Faisal Specialist Hospital and Research Center)

  • Jana Vandrovcova

    (UCL Queen Square Institute of Neurology)

  • David Murphy

    (UCL Queen Square Institute of Neurology)

  • Anne-Claire Richard

    (Department of Genetics and CNRMAJ)

  • Olivier Quenez

    (Department of Genetics and CNRMAJ)

  • Antoine Bonnevalle

    (Department of Genetics and CNRMAJ)

  • M. Natalia Zanetti

    (UCL Queen Square Institute of Neurology)

  • Rauan Kaiyrzhanov

    (UCL Queen Square Institute of Neurology
    South Kazakhstan Medical Academy Shymkent)

  • Vincenzo Salpietro

    (UCL Queen Square Institute of Neurology)

  • Stephanie Efthymiou

    (UCL Queen Square Institute of Neurology)

  • Lucia V. Schottlaender

    (UCL Queen Square Institute of Neurology
    CONICET-Universidad Austral
    Hospital Universitario Austral, Universidad Austral)

  • Heba Morsy

    (UCL Queen Square Institute of Neurology
    Alexandria University)

  • Annarita Scardamaglia

    (UCL Queen Square Institute of Neurology)

  • Ambreen Tariq

    (UCL Queen Square Institute of Neurology)

  • Alistair T. Pagnamenta

    (Wellcome Centre for Human Genetics)

  • Ajia Pennavaria

    (University of Bergen)

  • Liv S. Krogstad

    (University of Bergen)

  • Åse K. Bekkelund

    (University of Bergen)

  • Alessia Caiella

    (University of Bergen)

  • Nina Glomnes

    (University of Bergen
    University of Bergen)

  • Kirsten M. Brønstad

    (University of Bergen)

  • Sandrine Tury

    (Université de Montpellier, CNRS)

  • Andrés Moreno De Luca

    (Autism & Developmental Medicine Institute, Geisinger
    Kingston Health Sciences Centre, Queen’s University Faculty of Health Sciences)

  • Anne Boland-Auge

    (Centre National de Recherche en Génomique Humaine (CNRGH))

  • Robert Olaso

    (Centre National de Recherche en Génomique Humaine (CNRGH))

  • Jean-François Deleuze

    (Centre National de Recherche en Génomique Humaine (CNRGH))

  • Mathieu Anheim

    (Strasbourg University Hospital
    Strasbourg University
    University of Strasbourg)

  • Benjamin Cretin

    (Strasbourg University Hospital
    Strasbourg University
    University of Strasbourg)

  • Barbara Vona

    (University Medical Center Göttingen
    University Medical Center Göttingen)

  • Fahad Alajlan

    (King Faisal Specialist Hospital and Research Center)

  • Firdous Abdulwahab

    (King Faisal Specialist Hospital and Research Center)

  • Jean-Luc Battini

    (Université de Montpellier, CNRS)

  • Rojan İpek

    (Dicle University)

  • Peter Bauer

    (Centogene GmbH)

  • Giovanni Zifarelli

    (Centogene GmbH)

  • Serdal Gungor

    (Division of Pediatric Neurology)

  • Semra Hiz Kurul

    (Department of Paediatric Neurology)

  • Hanns Lochmuller

    (The Ottawa Hospital
    University of Ottawa
    Medical Center–University of Freiburg, Faculty of Medicine)

  • Sahar I. Da’as

    (Sidra Medicine
    Hamad Bin Khalifa University)

  • Khalid A. Fakhro

    (Sidra Medicine
    Hamad Bin Khalifa University
    Weill Cornell Medical College)

  • Alicia Gómez-Pascual

    (University of Murcia, Campus Espinardo)

  • Juan A. Botía

    (University of Murcia, Campus Espinardo)

  • Nicholas W. Wood

    (UCL Queen Square Institute of Neurology
    The National Hospital for Neurology and Neurosurgery)

  • Rita Horvath

    (University of Cambridge)

  • Andreas M. Ernst

    (Yale School of Medicine
    University of California San Diego)

  • James E. Rothman

    (Yale School of Medicine
    UCL Queen Square Institute of Neurology)

  • Meriel McEntagart

    (St George’s University Hospitals)

  • Yanick J. Crow

    (INSERM UMR 1163
    University of Edinburgh)

  • Fowzan S. Alkuraya

    (King Faisal Specialist Hospital and Research Center
    Alfaisal University)

  • Gaël Nicolas

    (Department of Genetics and CNRMAJ)

  • Thomas Arnesen

    (University of Bergen
    Haukeland University Hospital)

  • Henry Houlden

    (UCL Queen Square Institute of Neurology
    The National Hospital for Neurology and Neurosurgery)

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.

Suggested Citation

  • 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 , 2024. "Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46354-0
    DOI: 10.1038/s41467-024-46354-0
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    References listed on IDEAS

    as
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    3. Eric Linster & Francy L. Forero Ruiz & Pavlina Miklankova & Thomas Ruppert & Johannes Mueller & Laura Armbruster & Xiaodi Gong & Giovanna Serino & Matthias Mann & Rüdiger Hell & Markus Wirtz, 2022. "Cotranslational N-degron masking by acetylation promotes proteome stability in plants," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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