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

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

  • Am J Hum Genet. 2017 Oct 5;101(4):525-538. doi: 10.1016/j.ajhg.2017.08.015.
René G Feichtinger 1,  Monika Oláhová 2,  Yoshihito Kishita 3,  Caterina Garone 4,  Laura S Kremer 5,  Mikako Yagi 6,  Takeshi Uchiumi 6,  Alexis A Jourdain 7,  Kyle Thompson 2,  Aaron R D'Souza 8,  Robert Kopajtich 9,  Charlotte L Alston 2,  Johannes Koch 1,  Wolfgang Sperl 1,  Elisa Mastantuono 5,  Tim M Strom 5,  Saskia B Wortmann 10,  Thomas Meitinger 11,  Germaine Pierre 12,  Patrick F Chinnery 8,  Zofia M Chrzanowska-Lightowlers 2,  Robert N Lightowlers 2,  Salvatore DiMauro 13,  Sarah E Calvo 7,  Vamsi K Mootha 7,  Maurizio Moggio 14,  Monica Sciacco 14,  Giacomo P Comi 15,  Dario Ronchi 15,  Kei Murayama 16,  Akira Ohtake 17,  Pedro Rebelo-Guiomar 18,  Masakazu Kohda 3,  Dongchon Kang 6,  Johannes A Mayr 1,  Robert W Taylor 2,  Yasushi Okazaki 3,  Michal Minczuk 8,  Holger Prokisch 19
Affiliations

Affiliations

  • 1 Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
  • 2 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  • 3 Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan; Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan.
  • 4 Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust, MRC Building, Cambridge CB2 0XY, UK; Department of Neurology, Columbia University Medical Center, New York, NY 10032-3784, USA.
  • 5 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 6 Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
  • 7 Howard Hughes Medical Institute, Department of Molecular Biology, Center for Genome Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 8 Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust, MRC Building, Cambridge CB2 0XY, UK.
  • 9 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 10 Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 11 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
  • 12 South West Regional Metabolic Department, Bristol Royal Hospital for Children, Bristol BS1 3NU, UK.
  • 13 Department of Neurology, Columbia University Medical Center, New York, NY 10032-3784, USA.
  • 14 Neuromuscular Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.
  • 15 Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.
  • 16 Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan.
  • 17 Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
  • 18 Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust, MRC Building, Cambridge CB2 0XY, UK; Graduate Program in Areas of Basic and Applied Biology, University of Porto, 4099-002 Porto, Portugal.
  • 19 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany. Electronic address: prokisch@helmholtz-muenchen.de.
PMID: 28942965 DOI: 10.1016/j.ajhg.2017.08.015
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.

Keywords

MAM33; PEO; lactate; mitochondria; multiple mtDNA deletions; myopathy; oxidative phosphorylation; p32; progressive external ophthalmoplegia.

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