Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies
| Autor: | Feichtinger R. G., Olahova 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. |
|---|---|
| Přispěvatelé: | Garone, Caterina [0000-0003-4928-1037], Chinnery, Patrick [0000-0002-7065-6617], Minczuk, Michal [0000-0001-8242-1420], Apollo - University of Cambridge Repository, Feichtinger R.G., Olahova 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. |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Mitochondrial Diseases Protein Conformation Sequence Homology Severity of Illness Index Cohort Studies Mice Mitochondrial Disease Age of Onset Cells Cultured Allele multiple mtDNA deletions Middle Aged Pedigree mitochondria Child Preschool Adult Aged Alleles Amino Acid Sequence Animals Cardiomyopathies/complications Cardiomyopathies/genetics Cardiomyopathies/pathology Carrier Proteins/chemistry Carrier Proteins/genetics Carrier Proteins/metabolism DNA Mitochondrial Electron Transport/physiology Embryo Mammalian/metabolism Embryo Mammalian/pathology Female Fibroblasts/metabolism Fibroblasts/pathology Humans Infant Newborn Mitochondrial Diseases/complications Mitochondrial Diseases/genetics Mitochondrial Diseases/pathology Mitochondrial Proteins/chemistry Mitochondrial Proteins/genetics Mitochondrial Proteins/metabolism Mutation Oxidative Phosphorylation Young Adult MAM33 PEO lactate myopathy oxidative phosphorylation p32 progressive external ophthalmoplegia multiple mtDNA deletion Fibroblast Cardiomyopathies Human Article Electron Transport Mitochondrial Proteins Mitochondrial Protein Cardiomyopathie Animal Fibroblasts Embryo Mammalian Cohort Studie Carrier Protein Carrier Proteins |
| Zdroj: | American Journal of Human Genetics American journal of human genetics, vol. 101, no. 4, pp. 525-538 |
| ISSN: | 1537-6605 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|