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 individualsâ samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbpâ/âmouse 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 C1qbpâ/âMEFs. 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.
Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies / R.G. Feichtinger, M. Oláhová, Y. Kishita, C. Garone, L.S. Kremer, M. Yagi, T. Uchiumi, A.A. Jourdain, K. Thompson, A.R. D'Souza, R. Kopajtich, C.L. Alston, J. Koch, W. Sperl, E. Mastantuono, T.M. Strom, S.B. Wortmann, T. Meitinger, G. Pierre, P.F. Chinnery, Z.M. Chrzanowska-Lightowlers, R.N. Lightowlers, S. Dimauro, S.E. Calvo, V.K. Mootha, M. Moggio, M. Sciacco, G.P. Comi, D. Ronchi, K. Murayama, A. Ohtake, P. Rebelo-Guiomar, M. Kohda, D. Kang, J.A. Mayr, R.W. Taylor, Y. Okazaki, M. Minczuk, H. Prokisch. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 101:4(2017), pp. 525-538.
|Titolo:||Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies|
COMI, GIACOMO PIETRO [Data Curation]
RONCHI, DARIO [Investigation]
|Parole Chiave:||lactate; MAM33; mitochondria; multiple mtDNA deletions; myopathy; oxidative phosphorylation; p32; PEO; progressive external ophthalmoplegia; Adult; 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; Oxidative Phosphorylation; Pedigree; Protein Conformation; Sequence Homology; Severity of Illness Index; Young Adult; Mutation; Genetics; Genetics (clinical)|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
|Data di pubblicazione:||2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ajhg.2017.08.015|
|Appare nelle tipologie:||01 - Articolo su periodico|