Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders
Year: 2025
Type: article
Abstract: ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.
Source: EMBO Molecular Medicine
Authors: Sara M Fielder, Marisa W Friederich, Daniella H Hock, Jessie R Zhang, Liana M Valin, Jill A Rosenfeld, Kevin T A Booth, Natasha J Brown, Rocio Rius, Tanavi Sharma, Liana N Semcesen, Kim C Worley, Lindsay C Burrage, Kayla Treat, Tara Samson, Sarah Govert, Sara DaCunha, Weimin Yuan, Jian Chen, Jacob Lesinski, Hieu Hoang, Stephanie A Morrison, Farah A Ladha, Roxanne A Van Hove, Cole R Michel, Richard Reisdorph, Eric Tycksen, Dustin Baldridge, Gary A Silverman, Claudia Soler-Alfonso, Erin Conboy, Francesco Vetrini, Lisa Emrick, William J Craigen, Undiagnosed Diseases Network, Stephen M Sykes, David A Stroud, Johan L K Van Hove, Tim Schedl, Stephen C Pak
Institutions: Washington University in St. Louis, Children's Hospital Colorado, University of Colorado Anschutz, University of Colorado Denver, The University of Melbourne, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Baylor College of Medicine, Indiana University Indianapolis, Indiana University School of Medicine, Garvan Institute of Medical Research, UNSW Sydney, Texas Children's Hospital, Genome Technology Access Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
Funders: Armstrong Foundation, Children's Hospital Colorado, Washington University in St. Louis, Children's Discovery Institute, Children’s Hospital of Wisconsin Research Institute, Children's Hospital Foundation, Murdoch Children's Research Institute, Royal Children's Hospital Foundation, Rare Diseases Clinical Research Network, State Government of Victoria, Mito Foundation, Pierce Armstrong Foundation, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Medical Research Council, National Health and Medical Research Council, National Human Genome Research Institute, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Office of Research Infrastructure Programs, National Institutes of Health, Common Fund, Medical Research Future Fund
Awards: G1095902784, G1270721750, G1400896056, Building a foundation for equitable population-scale genomic medicine, G1994913649, BCM Clinical Site for an Undiagnosed Disease Network (UDN) Phase II (U01), G3199122987, Stem cell versus meiotic fate decision in C. elegans, Developing a multi-omics platform for the diagnosis of mitochondrial disease, Fusion Lumos Orbitrap System for Quantitative Proteomics and Metabolomics Applications, G4301318905, G546999678, The North American Mitochondrial Disease Consortium (NAMDC), G6744361651, Clinical Sequencing Core Facility for the Undiagnosed Diseases Network (UDN), Baylor College of Medicine Intellectual and Developmental Disabilities Research Center, G748625499, G7684002728, Multi-organism platform for functional analysis of Undiagnosed Diseases Network (UDN) variants, Control of germline stem cells and the switch to meiotic development in C. elegans, G9000028377, Caenorhabditis Genetics Center, UDN Diagnostic Center of Excellence at Baylor College of Medicine, G961674178
OpenAlex ID: W4413683999