Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
| dc.authorid | NICOLAS, Gaël/0000-0002-1671-8274 | |
| dc.authorid | Vona, Barbara/0000-0002-6719-3447 | |
| dc.authorid | Moreno De Luca, Andres/0000-0002-2732-4043 | |
| dc.authorid | Arnesen, Thomas/0000-0002-3005-147X | |
| dc.authorid | Efthymiou, Stephanie/0000-0003-4900-9877 | |
| dc.authorid | Maroofian, Reza/0000-0001-6763-1542 | |
| dc.authorid | Houlden, Henry/0000-0002-2866-7777 | |
| dc.authorwosid | NICOLAS, Gaël/D-7611-2013 | |
| dc.authorwosid | Vona, Barbara/H-7377-2019 | |
| dc.authorwosid | Moreno De Luca, Andres/AAB-3570-2021 | |
| dc.authorwosid | Arnesen, Thomas/J-7139-2017 | |
| dc.authorwosid | Wood, Nicholas/C-2505-2009 | |
| dc.contributor.author | Chelban, Viorica | |
| dc.contributor.author | Aksnes, Henriette | |
| dc.contributor.author | Maroofian, Reza | |
| dc.contributor.author | LaMonica, Lauren C. | |
| dc.contributor.author | Seabra, Luis | |
| dc.contributor.author | Siggervag, Anette | |
| dc.contributor.author | Devic, Perrine | |
| dc.date.accessioned | 2024-08-04T20:55:10Z | |
| dc.date.available | 2024-08-04T20:55:10Z | |
| dc.date.issued | 2024 | |
| dc.department | İnönü Üniversitesi | en_US |
| dc.description.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. | en_US |
| dc.description.sponsorship | National Institute for Health and Care Research; NHS England; Wellcome Trust [221951/Z/20/Z]; Cancer Research UK; Medical Research Council; European Union [2014-19]; MRC [VO 2138/7-1, BRC-1215-20014, ABN 540868]; GP2 ASAP; Michael J Fox Foundation (MJFF); National Institute for Health Research University College London Hospitals Biomedical Research Center; European Regional Development Fund (ERDF); Rosetree Trust; Agence Nationale pour la Recherche; MSA Trust; National Research Agency (France); MSA Coalition; Deutsche Forschungsgemeinschaft (DFG) through the Multiscale Bioimaging Cluster of Excellence (MBExC); Brain Research UK; DFG; Sparks GOSH Charity; NIH; Muscular Dystrophy UK (MDUK); Association of British Neurologists' Academic Clinical Training Research Fellowship [565908]; Guarantors of Brain [249843]; Research Council of Norway [F-12540]; Norwegian Health Authorities of Western Norway [171752-PR-2009-0222]; Norwegian Cancer Society [772039]; European Research Council (ERC) [109915/Z/15/Z]; Wellcome Trust Investigator [MR/N025431/1]; Medical Research Council (UK) [MR/V009346/1, 309548]; European Research Council [MR/N027302/1]; Newton Fund (UK/Turkey) [G100142]; Adden brookes Charitable Trust [MR/S005021/1]; Evelyn Trust; Stoneygate Trust; Lily Foundation; MRC strategic award to establish an International Center for Genomic Medicine in Neuromuscular Diseases (ICGNMD) [BRC-1215-20014]; NIHR Cambridge Biomedical Research Center [ANR-17-CE14-0008-01]; French National Research Agency (CALCIPHOS) [ANR-10-INBS-09]; Conseil Regional de Haute-Normandie (APERC); European Union (Recherche Innovation Normandie - RIN 2018); [MC_UU_00035/11]; [ANR-10-IAHU-01]; [469177153]; [R35 GM142433]; [779257]; [MR/S01165X/1]; [ANR-17-CE14-0008-02] | en_US |
| dc.description.sponsorship | The authors would like to thank the participants and their families for their essential help with this work. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health and Care Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded the research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No 779257. H.H. was supported by the MRC (MR/S01165X/1, MR/S005021/1, MRC ICGNMD), Wellcome Trust (221951/Z/20/Z), GP2 ASAP, Michael J Fox Foundation (MJFF), The National Institute for Health Research University College London Hospitals Biomedical Research Center, Rosetree Trust, MSA Trust, MSA Coalition, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK). V.C. was supported by the Association of British Neurologists' Academic Clinical Training Research Fellowship (grant ABN 540868) and The Guarantors of Brain (grant 565908). Members of the Arnesen lab are acknowledged for helpful inputs to this study. T.A. acknowledges support from the Research Council of Norway (Project 249843), the Norwegian Health Authorities of Western Norway (Project F-12540), the Norwegian Cancer Society (Project 171752-PR-2009-0222), and the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program under Grant 772039. Microscopy using a Leica TCS SP8 STED 3x confocal microscope was performed at the Molecular Imaging Center (MIC), Department of Biomedicine, University of Bergen. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation and an MRC strategic award to establish an International Center for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1, the NIHR Cambridge Biomedical Research Center (BRC-1215-20014). G.N. acknowledges support from the French National Research Agency (CALCIPHOS, ANR-17-CE14-0008-02), Conseil Regional de Haute-Normandie (APERC 2014 no. 2014-19 in the context of Appel d'Offres Jeunes Chercheurs, CHU de Rouen), Region Normandie and the European Union (Recherche Innovation Normandie - RIN 2018; Europe is involved in Normandie with the European Regional Development Fund (ERDF)). Part of this work is a collaboration between CEA-DRF-Jacob-CNRGH-CHU de Rouen. J.F.D. acknowledges support for France Genomique National infrastructure, funded as part of the Investissements d'Avenir program managed by the Agence Nationale pour la Recherche (contract ANR-10-INBS-09). J.L.B was supported by the French National Research Agency (CALCIPHOS, ANR-17-CE14-0008-01). Y.J.C. acknowledges a state subsidy managed by the National Research Agency (France) under the Investments for the Future (ANR-10-IAHU-01) and funding from the MRC (Grant code: MC_UU_00035/11). B.V.; acknowledges support from the Deutsche Forschungsgemeinschaft (DFG) through the Multiscale Bioimaging Cluster of Excellence (MBExC) and DFG VO 2138/7-1 grant 469177153. BV is a member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). NIH R35 GM142433 to A.M.E. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. | en_US |
| dc.identifier.doi | 10.1038/s41467-024-46354-0 | |
| dc.identifier.issn | 2041-1723 | |
| dc.identifier.issue | 1 | en_US |
| dc.identifier.pmid | 38480682 | en_US |
| dc.identifier.scopus | 2-s2.0-85187731525 | en_US |
| dc.identifier.scopusquality | Q1 | en_US |
| dc.identifier.uri | https://doi.org/10.1038/s41467-024-46354-0 | |
| dc.identifier.uri | https://hdl.handle.net/11616/101878 | |
| dc.identifier.volume | 15 | en_US |
| dc.identifier.wos | WOS:001228274200020 | en_US |
| dc.identifier.wosquality | N/A | en_US |
| dc.indekslendigikaynak | Web of Science | en_US |
| dc.indekslendigikaynak | Scopus | en_US |
| dc.indekslendigikaynak | PubMed | en_US |
| dc.language.iso | en | en_US |
| dc.publisher | Nature Portfolio | en_US |
| dc.relation.ispartof | Nature Communications | en_US |
| dc.relation.publicationcategory | Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı | en_US |
| dc.rights | info:eu-repo/semantics/openAccess | en_US |
| dc.subject | Basal Ganglia Calcification | en_US |
| dc.subject | Alpha-Acetyltransferase | en_US |
| dc.subject | Molecular Determinants | en_US |
| dc.subject | Mutations | en_US |
| dc.subject | Gene | en_US |
| dc.subject | Expression | en_US |
| dc.subject | Slc20a2 | en_US |
| dc.subject | Prevalence | en_US |
| dc.subject | Framework | en_US |
| dc.subject | Disease | en_US |
| dc.title | Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications | en_US |
| dc.type | Article | en_US |
