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

René G. Feichtinger, Monika Oláhová, Yoshihito Kishita, Caterina Garone, Laura S. Kremer, Mikako Yagi, Takeshi Uchiumi, Alexis A. Jourdain, Kyle Thompson, Aaron R. D'Souza, Robert Kopajtich, Charlotte L. Alston, Johannes Koch, Wolfgang Sperl, Elisa Mastantuono, Tim M. Strom, Saskia B. Wortmann, Thomas Meitinger, Germaine Pierre, Patrick F. ChinneryZofia M. Chrzanowska-Lightowlers, Robert N. Lightowlers, Salvatore DiMauro, Sarah E. Calvo, Vamsi K. Mootha, Maurizio Moggio, Monica Sciacco, Giacomo P. Comi, Dario Ronchi, Kei Murayama, Akira Ohtake, Pedro Rebelo-Guiomar, Masakazu Kohda, Dongchon Kang, Johannes A. Mayr, Robert W. Taylor, Yasushi Okazaki, Michal Minczuk, Holger Prokisch

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)525-538
Number of pages14
JournalAmerican journal of human genetics
Volume101
Issue number4
DOIs
Publication statusPublished - Oct 5 2017

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Chronic Progressive External Ophthalmoplegia
Oxidative Phosphorylation
Muscular Diseases
Electron Transport
Cardiomyopathies
Cytochrome-c Oxidase Deficiency
Fibroblasts
Complement C1
Mitochondrial Diseases
Lactic Acidosis
Mutation
Mitochondrial Proteins
Organelle Biogenesis
Enzymes
Mitochondrial DNA
Energy Metabolism
Carrier Proteins
Proteins
Apoptosis
Inflammation

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies. / Feichtinger, René G.; Oláhová, Monika; Kishita, Yoshihito; Garone, Caterina; Kremer, Laura S.; Yagi, Mikako; Uchiumi, Takeshi; Jourdain, Alexis A.; Thompson, Kyle; D'Souza, Aaron R.; Kopajtich, Robert; Alston, Charlotte L.; Koch, Johannes; Sperl, Wolfgang; Mastantuono, Elisa; Strom, Tim M.; Wortmann, Saskia B.; Meitinger, Thomas; Pierre, Germaine; Chinnery, Patrick F.; Chrzanowska-Lightowlers, Zofia M.; Lightowlers, Robert N.; DiMauro, Salvatore; Calvo, Sarah E.; Mootha, Vamsi K.; Moggio, Maurizio; Sciacco, Monica; Comi, Giacomo P.; Ronchi, Dario; Murayama, Kei; Ohtake, Akira; Rebelo-Guiomar, Pedro; Kohda, Masakazu; Kang, Dongchon; Mayr, Johannes A.; Taylor, Robert W.; Okazaki, Yasushi; Minczuk, Michal; Prokisch, Holger.

In: American journal of human genetics, Vol. 101, No. 4, 05.10.2017, p. 525-538.

Research output: Contribution to journalArticle

Feichtinger, 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, M & Prokisch, H 2017, 'Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies', American journal of human genetics, vol. 101, no. 4, pp. 525-538. https://doi.org/10.1016/j.ajhg.2017.08.015
Feichtinger, René G. ; Oláhová, Monika ; Kishita, Yoshihito ; Garone, Caterina ; Kremer, Laura S. ; Yagi, Mikako ; Uchiumi, Takeshi ; Jourdain, Alexis A. ; Thompson, Kyle ; D'Souza, Aaron R. ; Kopajtich, Robert ; Alston, Charlotte L. ; Koch, Johannes ; Sperl, Wolfgang ; Mastantuono, Elisa ; Strom, Tim M. ; Wortmann, Saskia B. ; Meitinger, Thomas ; Pierre, Germaine ; Chinnery, Patrick F. ; Chrzanowska-Lightowlers, Zofia M. ; Lightowlers, Robert N. ; DiMauro, Salvatore ; Calvo, Sarah E. ; Mootha, Vamsi K. ; Moggio, Maurizio ; Sciacco, Monica ; Comi, Giacomo P. ; Ronchi, Dario ; Murayama, Kei ; Ohtake, Akira ; Rebelo-Guiomar, Pedro ; Kohda, Masakazu ; Kang, Dongchon ; Mayr, Johannes A. ; Taylor, Robert W. ; Okazaki, Yasushi ; Minczuk, Michal ; Prokisch, Holger. / Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies. In: American journal of human genetics. 2017 ; Vol. 101, No. 4. pp. 525-538.
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abstract = "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.",
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T1 - Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

AU - Feichtinger, René G.

AU - Oláhová, Monika

AU - Kishita, Yoshihito

AU - Garone, Caterina

AU - Kremer, Laura S.

AU - Yagi, Mikako

AU - Uchiumi, Takeshi

AU - Jourdain, Alexis A.

AU - Thompson, Kyle

AU - D'Souza, Aaron R.

AU - Kopajtich, Robert

AU - Alston, Charlotte L.

AU - Koch, Johannes

AU - Sperl, Wolfgang

AU - Mastantuono, Elisa

AU - Strom, Tim M.

AU - Wortmann, Saskia B.

AU - Meitinger, Thomas

AU - Pierre, Germaine

AU - Chinnery, Patrick F.

AU - Chrzanowska-Lightowlers, Zofia M.

AU - Lightowlers, Robert N.

AU - DiMauro, Salvatore

AU - Calvo, Sarah E.

AU - Mootha, Vamsi K.

AU - Moggio, Maurizio

AU - Sciacco, Monica

AU - Comi, Giacomo P.

AU - Ronchi, Dario

AU - Murayama, Kei

AU - Ohtake, Akira

AU - Rebelo-Guiomar, Pedro

AU - Kohda, Masakazu

AU - Kang, Dongchon

AU - Mayr, Johannes A.

AU - Taylor, Robert W.

AU - Okazaki, Yasushi

AU - Minczuk, Michal

AU - Prokisch, Holger

PY - 2017/10/5

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N2 - 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.

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