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Nasca, A.* ; Mencacci, N.E.* ; Invernizzi, F.* ; Zech, M. ; Sarmiento, I.J.K.* ; Legati, A.* ; Frascarelli, C.* ; Bustos, B.I.* ; Romito, L.M.* ; Krainc, D.* ; Winkelmann, J. ; Carecchio, M.* ; Nardocci, N.* ; Zorzi, G.* ; Prokisch, H. ; Lubbe, S.J.* ; Garavaglia, B.* ; Ghezzi, D.*

Variants in ATP5F1B are associated with dominantly inherited dystonia.

Brain 146, 2730-2738 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Atp5f1b ; Case Report ; Dystonia ; Incomplete Penetrance ; Mitochondrial Atp Synthase
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Journal Brain: A Journal of Neurology
Quellenangaben Volume: 146, Issue: 7, Pages: 2730-2738 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants German Research Foundation
Parkinson's Foundation
Italian Ministry of Health (RRC)
Mariani Foundation
European Joint Programme on Rare Diseases (EJP RD) project GENOMIT (German Federal Ministry of Education and Research)
European Joint Programme on Rare Diseases (EJP RD) project GENOMIT (Italian Ministry of Health)
ERA PerMed project PerMiM (German Federal Ministry of Education and Research)
ERA PerMed project PerMiM (Italian Ministry of Health)