Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies.

TitleBiallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies.
Publication TypeJournal Article
Year of Publication2017
AuthorsFeichtinger, RG, Oláhová, 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, MA, Prokisch, H
JournalAm J Hum Genet
Date Published2017 Oct 05
KeywordsAdult, Age of Onset, Aged, Alleles, Amino Acid Sequence, Animals, Cardiomyopathies, Carrier Proteins, Cells, Cultured, Child, Preschool, Cohort Studies, DNA, Mitochondrial, Electron Transport, Embryo, Mammalian, Female, Fibroblasts, Humans, Infant, Newborn, Male, Mice, Middle Aged, Mitochondrial Diseases, Mitochondrial Proteins, Mutation, Oxidative Phosphorylation, Pedigree, Protein Conformation, Sequence Homology, Severity of Illness Index, Young Adult

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.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2017.08.015
PubMed ID28942965
PubMed Central IDPMC5630164
Grant List / / Wellcome Trust / United Kingdom
R01 GM077465 / GM / NIGMS NIH HHS / United States
R35 GM122455 / GM / NIGMS NIH HHS / United States