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

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_C1BEEDEE0B33
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies.
Périodique
American journal of human genetics
Auteur⸱e⸱s
Feichtinger R.G., Oláhová M., Kishita Y., Garone C., Kremer L.S., Yagi M., Uchiumi T., Jourdain A.A., Thompson K., D'Souza A.R., Kopajtich R., Alston C.L., Koch J., Sperl W., Mastantuono E., Strom T.M., Wortmann S.B., Meitinger T., Pierre G., Chinnery P.F., Chrzanowska-Lightowlers Z.M., Lightowlers R.N., DiMauro S., Calvo S.E., Mootha V.K., Moggio M., Sciacco M., Comi G.P., Ronchi D., Murayama K., Ohtake A., Rebelo-Guiomar P., Kohda M., Kang D., Mayr J.A., Taylor R.W., Okazaki Y., Minczuk M., Prokisch H.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
05/10/2017
Peer-reviewed
Oui
Volume
101
Numéro
4
Pages
525-538
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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 <sup>-/-</sup> 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 <sup>-/-</sup> 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.
Mots-clé
Adult, Age of Onset, Aged, Alleles, Amino Acid Sequence, Animals, Cardiomyopathies/complications, Cardiomyopathies/genetics, Cardiomyopathies/pathology, Carrier Proteins/chemistry, Carrier Proteins/genetics, Carrier Proteins/metabolism, Cells, Cultured, Child, Preschool, Cohort Studies, DNA, Mitochondrial, Electron Transport/physiology, Embryo, Mammalian/metabolism, Embryo, Mammalian/pathology, Female, Fibroblasts/metabolism, Fibroblasts/pathology, Humans, Infant, Newborn, Male, Mice, Middle Aged, Mitochondrial Diseases/complications, Mitochondrial Diseases/genetics, Mitochondrial Diseases/pathology, Mitochondrial Proteins/chemistry, Mitochondrial Proteins/genetics, Mitochondrial Proteins/metabolism, Mutation, Oxidative Phosphorylation, Pedigree, Protein Conformation, Sequence Homology, Severity of Illness Index, Young Adult, MAM33, PEO, lactate, mitochondria, multiple mtDNA deletions, myopathy, oxidative phosphorylation, p32, progressive external ophthalmoplegia
Pubmed
Web of science
Open Access
Oui
Création de la notice
13/04/2021 17:25
Dernière modification de la notice
08/02/2022 7:36
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