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 patients diagnosed with mitochondrial disease and/or dystonia 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 5 patients. RESULTS: We present 10 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 3 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 patient samples 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. ANN NEUROL 2022;91:225-237.

Broad Center for Mendelian Genomics Broad Institute of MIT and Harvard Cambridge MA

Children's Hospital Kreiskliniken Reutlingen Germany

Département de Biochimie et Génétique Centre Hospitalier Universitaire d'Angers Angers France

Department of General Pediatrics Neonatology and Pediatric Cardiology University Children's Hospital Medical Faculty Heinrich Heine University Düsseldorf Germany

Department of Genetics Washington University School of Medicine St Louis MO

Department of Medical Genetic Diskapi Yildirim Beyazit Training and Research Hospital Ankara Turkey

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology Medical University of Innsbruck Innsbruck Austria

Department of Neuropediatrics and Muscle Disorders University Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Department of Pediatric Neurology University Children's Hospital Zurich University of Zurich Zurich Switzerland

Department of Pediatrics Washington University School of Medicine St Louis MO

Departments of Child Health Neurology and Cellular and Molecular Medicine and Program in Genetics University of Arizona College of Medicine Phoenix Phoenix AZ

Harvard Medical School and Center for Genomic Medicine Massachusetts General Hospital Boston and Laboratory for Molecular Medicine Partners Healthcare Personalized Medicine Cambridge MA

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Kinderkrankenhaus St Marien gGmbH Zentrum für Kinder und Jugendmedizin Landshut Germany

Lehrstuhl für Neurogenetik Technische Universität München Munich Germany

Munich Cluster for Systems Neurology Munich Germany

Pediatric Movement Disorders Program Division of Pediatric Neurology Barrow Neurological Institute Phoenix Children's Hospital Phoenix AZ

Pediatric Neurology Department CHU Clocheville Tours France

Program in Medical and Population Genetics Broad Institute Cambridge MA

Radboud Center for Mitochondrial Medicine Department of Pediatrics Amalia Children's Hospital Radboud UMC Nijmegen The Netherlands

Radboud Centre for Mitochondrial Medicine Department of Paediatrics Radboud Institute for Molecular Life Sciences Radboud University Nijmegen Medical Centre Nijmegen Nijmegen The Netherlands

Technical University of Munich School of Medicine Institute of Human Genetics Munich Germany

Unité Mixte de Recherche MITOVASC CNRS 6015 INSERM 1083 Université d'Angers Angers France

University Children's Hospital Paracelsus Medical University Salzburg Austria

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