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

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.

• Publication year

  2017

• Venue

  American Journal of Human Genetics

• Publication date

  2017-09-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.ajhg.2017.08.015PMID 28942965PMCID 5630164
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Complementation with wild-type C1qbp restores OXPHOS protein levels and mitochondrial enzyme activities in C1qbp−/− mouse embryonic fibroblasts.

  Confidence 0.95

  All you need is Python (5d7gwfm5zu) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• Decreased steady-state C1QBP levels lead to combined respiratory-chain enzyme deficiency of complexes I, III, and IV.

  Confidence 0.90

  All you need is Python (5d7gwfm5zu) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• Biallelic mutations in C1QBP cause severe neonatal cardiomyopathy or later-onset myopathy and progressive external ophthalmoplegia.

  Confidence 0.95

  All you need is Python (5d7gwfm5zu) extraction뀨 (7c402c1b98) reviewB (s683577b42) review

• biallelic c1qbp mutations

  genetic variants

  Genetic variants in both alleles of the C1QBP gene identified in individuals with mitochondrial energy metabolism defects.

  All you need is Python (5d7gwfm5zu) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• c1qbp

  proteins

  A multi-compartmental protein primarily localized in the mitochondrial matrix involved in ribosome biogenesis and apoptosis.

  Aliases: p32

  All you need is Python (5d7gwfm5zu) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• combined respiratory-chain deficiencies

  metabolic disorders

  A deficiency affecting multiple mitochondrial respiratory chain enzyme complexes including I, III, and IV.

  All you need is Python (5d7gwfm5zu) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• mouse embryonic fibroblasts

  model systems

  Cells derived from mouse embryos used here to validate that wild-type C1qbp rescues OXPHOS function.

  Aliases: MEFs

  All you need is Python (5d7gwfm5zu) extraction뀨 (7c402c1b98) reviewB (s683577b42) review

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