TY - JOUR
T1 - Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes
AU - Zech, Michael
AU - Kopajtich, Robert
AU - Steinbrücker, Katja
AU - Bris, Céline
AU - Gueguen, Naig
AU - Feichtinger, René G.
AU - Achleitner, Melanie T.
AU - Duzkale, Neslihan
AU - Périvier, Maximilien
AU - Koch, Johannes
AU - Engelhardt, Harald
AU - Freisinger, Peter
AU - Wagner, Matias
AU - Brunet, Theresa
AU - Berutti, Riccardo
AU - Smirnov, Dmitrii
AU - Navaratnarajah, Tharsini
AU - Rodenburg, Richard J.T.
AU - Pais, Lynn S.
AU - Austin-Tse, Christina
AU - O'Leary, Melanie
AU - Boesch, Sylvia
AU - Jech, Robert
AU - Bakhtiari, Somayeh
AU - Jin, Sheng Chih
AU - Wilbert, Friederike
AU - Kruer, Michael C.
AU - Wortmann, Saskia B.
AU - Eckenweiler, Matthias
AU - Mayr, Johannes A.
AU - Distelmaier, Felix
AU - Steinfeld, Robert
AU - Winkelmann, Juliane
AU - Prokisch, Holger
N1 - Funding Information:
The authors would like to thank the patients and their families who took part in our study. This study was funded in part by a research grant from the Else Kröner‐Fresenius‐Stiftung as well as by in‐house institutional funding from Technische Universität München, Munich, Germany, Helmholtz Zentrum München, Munich, Germany, Medizinische Universität Innsbruck, Innsbruck, Austria, and Charles University, Prague, Czech Republic (PROGRES Q27). This study was also funded by the Czech Ministry of Education under grant AZV: NV19‐04‐00233 and under the frame of EJP RD, the European Joint Programme on Rare Diseases (EJP RD COFUND‐EJP No. 825575). M.Z. and J.W. receive research support from the German Research Foundation (DFG 458949627; ZE 1213/2‐1; WI 1820/14‐1). S.B. is a member of the European Reference Network for Rare Neurological Diseases – Project ID No. 739510. M.C.K. has received funding from the U.S. National Institute of Neurological Disorders & Stroke 1R01 NS106298. Analysis of Patient 7 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute grants UM1 HG008900 (with additional support from the National Eye Institute, and the National Heart, Lung and Blood Institute), U01 HG0011755, and R01 HG009141 and in part by grant number 2020‐224274 from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation. F.D. receives research support from the German Research Foundation (DI 1731/2‐2) and was supported by a grant from the “Elterninitiative Kinderkrebsklinik e.V.” (Düsseldorf; #701900167). The authors acknowledge support by the German Federal Ministry of Education and Research (BMBF, Bonn, Germany) awarded grant to the German Network for Mitochondrial Disorders (mitoNET, 01GM1906A), the German BMBF, the Austrian Science Funds (FWF), and Horizon2020 through the E‐Rare project GENOMIT (01GM1920A, I4695‐B, genomit.eu), and the ERA PerMed project PerMiM (01KU2016A, I4704‐B, permim.eu). We gratefully thank Jennifer Alban and Justine Faure (Angers, France) for their generous contribution with enzyme activity and immunoblotting analyses. Open Access funding enabled and organized by Projekt DEAL.
Funding Information:
The authors would like to thank the patients and their families who took part in our study. This study was funded in part by a research grant from the Else Kröner-Fresenius-Stiftung as well as by in-house institutional funding from Technische Universität München, Munich, Germany, Helmholtz Zentrum München, Munich, Germany, Medizinische Universität Innsbruck, Innsbruck, Austria, and Charles University, Prague, Czech Republic (PROGRES Q27). This study was also funded by the Czech Ministry of Education under grant AZV: NV19-04-00233 and under the frame of EJP RD, the European Joint Programme on Rare Diseases (EJP RD COFUND-EJP No. 825575). M.Z. and J.W. receive research support from the German Research Foundation (DFG 458949627; ZE 1213/2-1; WI 1820/14-1). S.B. is a member of the European Reference Network for Rare Neurological Diseases – Project ID No. 739510. M.C.K. has received funding from the U.S. National Institute of Neurological Disorders & Stroke 1R01 NS106298. Analysis of Patient 7 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute grants UM1 HG008900 (with additional support from the National Eye Institute, and the National Heart, Lung and Blood Institute), U01 HG0011755, and R01 HG009141 and in part by grant number 2020-224274 from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation. F.D. receives research support from the German Research Foundation (DI 1731/2-2) and was supported by a grant from the “Elterninitiative Kinderkrebsklinik e.V.” (Düsseldorf; #701900167). The authors acknowledge support by the German Federal Ministry of Education and Research (BMBF, Bonn, Germany) awarded grant to the German Network for Mitochondrial Disorders (mitoNET, 01GM1906A), the German BMBF, the Austrian Science Funds (FWF), and Horizon2020 through the E-Rare project GENOMIT (01GM1920A, I4695-B, genomit.eu), and the ERA PerMed project PerMiM (01KU2016A, I4704-B, permim.eu). We gratefully thank Jennifer Alban and Justine Faure (Angers, France) for their generous contribution with enzyme activity and immunoblotting analyses. Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123075612&partnerID=8YFLogxK
U2 - 10.1002/ana.26293
DO - 10.1002/ana.26293
M3 - Article
C2 - 34954817
AN - SCOPUS:85123075612
VL - 91
SP - 225
EP - 237
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 2
ER -