Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
Overview
and 6 other authors
Leopold Zeng11, Thomas Klopstock11,12,13, André Schaller14, Jing Liu8, David A. Stroud1,2,6, Holger Prokisch5,7,1515 affiliations
- Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Victorian Clinical Genetics Services, Parkville, VIC, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
- Department of Paediatrics, Division of Endocrinology, Diabetology and Metabolism, and Institute of Clinical Chemistry, Inselspital - University Hospital of Bern, University of Bern, Bern, Switzerland
- Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich, Germany
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia
- Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
- Cipher Gene Ltd, Chengdu, China
- University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University Hospital of Bern, University of Bern, Bern, Switzerland
- Division of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children’s Hospital, LMU Hospital, Ludwig-Maximilians-Universität, Munich, Germany
- Friedrich Baur Institute at the Department of Neurology, LMU University Hospital, LMU Munich, 80336 Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
- Department of Human Genetics, Inselspital - University Hospital of Bern, University Bern, Bern, Switzerland
- German Center for Child and Adolescent Health (DZKJ), Partner Site Munich, Munich, Germany
Abstract
NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.
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The raw genomic and proteomic data that support the findings of this study have not been deposited in a public repository due to human research ethics committee and institutional review board restrictions but are available, along with all other materials, from the corresponding authors on request. This project did not involve development of new code.
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 26 authors, 5 keywords, 16 MeSH terms, 13 funders, 36 references.
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This paper
Tan, N. B., Gautschi, M., Raum, M., Hock, D. H., Kopajtich, R., Wang, J., Qian, X., Sharma, T., Green, T. E., Nuoffer, J.-M., Bell, K. M., Pospieszny, K., Stait, T., Pike, C., Cao, M., White, S. M., Thorburn, D. R., Brunet, T., Wagner, M., . . . Prokisch, H. (2026). Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency. American journal of human genetics, 113(5), 1108-1121. https://
BibTeX
@article{tan2026bi,
author = {Tan, Natalie B. and Gautschi, Matthias and Raum, Michael and Hock, Daniella H. and Kopajtich, Robert and Wang, Jia and Qian, Xiao and Sharma, Tanavi and Green, Timothy E. and Nuoffer, Jean-Marc and Bell, Katrina M. and Pospieszny, Katarzyna and Stait, Tegan and Pike, Chloe and Cao, Michelle and White, Susan M. and Thorburn, David R. and Brunet, Theresa and Wagner, Matias and Müller-Felber, Wolfgang and Zeng, Leopold and Klopstock, Thomas and Schaller, André and Liu, Jing and Stroud, David A. and Prokisch, Holger},
title = {{Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency}},
journal = {American journal of human genetics},
year = {2026},
month = mar,
volume = {113},
number = {5},
pages = {1108--1121},
publisher = {Elsevier},
issn = {0002-9297},
doi = {10.1016/
url = {https://
pmid = {41916321},
pmcid = {PMC13277682}
}
RIS
TY - JOUR
AU - Tan, Natalie B.
AU - Gautschi, Matthias
AU - Raum, Michael
AU - Hock, Daniella H.
AU - Kopajtich, Robert
AU - Wang, Jia
AU - Qian, Xiao
AU - Sharma, Tanavi
AU - Green, Timothy E.
AU - Nuoffer, Jean-Marc
AU - Bell, Katrina M.
AU - Pospieszny, Katarzyna
AU - Stait, Tegan
AU - Pike, Chloe
AU - Cao, Michelle
AU - White, Susan M.
AU - Thorburn, David R.
AU - Brunet, Theresa
AU - Wagner, Matias
AU - Müller-Felber, Wolfgang
AU - Zeng, Leopold
AU - Klopstock, Thomas
AU - Schaller, André
AU - Liu, Jing
AU - Stroud, David A.
AU - Prokisch, Holger
TI - Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency
T2 - American journal of human genetics
J2 - Am J Hum Genet
PY - 2026
DA - 2026/
VL - 113
IS - 5
SP - 1108
EP - 1121
SN - 0002-9297
PB - Elsevier
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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