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Zech, M. ; Kopajtich, R. ; Steinbrücker, K.* ; Bris, C.* ; Gueguen, N.* ; Feichtinger, R.G.* ; Achleitner, M.T.* ; Duzkale, N.* ; Périvier, M.* ; Koch, J.* ; Engelhardt, H.* ; Freisinger, P.* ; Wagner, M. ; Brunet, T. ; Berutti, R. ; Smirnov, D. ; Navaratnarajah, T.* ; Rodenburg, R.J.T.* ; Pais, L.S.* ; Austin-Tse, C.* ; O'Leary, M.* ; Boesch, S.* ; Jech, R.* ; Bakhtiari, S.* ; Jin, S.C.* ; Wilbert, F.* ; Kruer, M.C.* ; Wortmann, S.B.* ; Eckenweiler, M.* ; Mayr, J.A.* ; Distelmaier, F.* ; Steinfeld, R.* ; Winkelmann, J. ; Prokisch, H.

Variants in mitochondrial ATP synthase cause variable neurologic phenotypes.

Ann. Neurol. 91, 225-237 (2022)
Postprint Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 mitochondrial-disease- and/or dystonia-diagnosed individuals and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from five patients. RESULTS: We present ten total individuals with biallelic or de-novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de-novo heterozygous missense variants in ATP5F1A, whereas another three were heterozygous for ATP5MC3 de-novo missense changes. Bioinformatics methods and populational data supported the variants` pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in cells bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETATION: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. This article is protected by copyright. All rights reserved.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mutations
ISSN (print) / ISBN 0364-5134
e-ISSN 1531-8249
Journal Annals of Neurology
Quellenangaben Volume: 91, Issue: 2, Pages: 225-237 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Silicon Valley Community Foundation
Chan Zuckerberg Initiative DAF
National Human Genome Research Institute (National Heart, Lung and Blood Institute)
National Human Genome Research Institute (National Eye Institute)
U.S. National Institute of Neurological Disorders Stroke
European Reference Network for Rare Neurological Diseases
Czech Ministry of Education under EJP RD, the European Joint Programme on Rare Diseases (EJP RD COFUND-EJP)
Czech Ministry of Education
Charles University, Prague, Czech Republic (PROGRES Q27)
Medizinische Universitat Innsbruck, Innsbruck, Austria
Helmholtz Zentrum Munchen, Munich, Germany
Technische Universitat Munchen, Munich, Germany
National Human Genome Research Institute
Projekt DEAL
ERA PerMed project PerMiM
Horizon2020 through the E-Rare project GENOMIT
Austrian Science Funds (FWF)
German BMBF
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)
"Elterninitiative Kinderkrebsklinik e.V." (Dusseldorf)
German Research Foundation
Else Kroner-Fresenius-Stiftung