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Lookup NU author(s): Dr Monika Olahova, Dr Kyle Thompson, Dr Charlotte Alston, Professor Patrick Chinnery, Professor Zofia Chrzanowska-LightowlersORCiD, Professor Robert Lightowlers, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Authors. Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp -/- mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp -/- MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.
Author(s): Feichtinger RG, Olahova M, Kishita Y, Garone C, Kremer LS, Yagi M, Uchiumi T, Jourdain AA, Thompson K, D'Souza AR, Kopajtich R, Alston CL, Koch J, Sperl W, Mastantuono E, Strom TM, Wortmann SB, Meitinger T, Pierre G, Chinnery PF, Chrzanowska-Lightowlers ZM, Lightowlers RN, DiMauro S, Calvo SE, Mootha VK, Moggio M, Sciacco M, Comi GP, Ronchi D, Murayama K, Ohtake A, Rebelo-Guiomar P, Kohda M, Kang D, Mayr JA, Taylor RW, Okazaki Y, Minczuk M, Prokisch H
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2017
Volume: 101
Issue: 4
Pages: 525-538
Print publication date: 05/10/2017
Online publication date: 21/09/2017
Acceptance date: 11/08/2017
Date deposited: 16/10/2017
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2017.08.015
DOI: 10.1016/j.ajhg.2017.08.015
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