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.
Highlights
Mitochondrial disorders are an extremely heterogeneous group of inborn errors of metabolism and encompass a wide range of clinical presentations, such that approximately 300 disease-associated genes have been identified to date.[1,2] Mitochondrial dysfunction mainly affects organs with high energy requirements, such as the brain, central nervous system, muscle, and heart
Screening of our in-house database of more than 10,000 wholeexome sequencing (WES) datasets of individuals with nonmitochondrial disease revealed no additional individual with biallelic rare variants in component 1 Q subcomponent-binding protein (C1QBP)
Filtering for genes coding for mitochondrial proteins in probands Subjects Individual 1 (S1)–S3 revealed that C1QBP was the only gene with biallelic variants.[34]
Summary
Mitochondrial disorders are an extremely heterogeneous group of inborn errors of metabolism and encompass a wide range of clinical presentations, such that approximately 300 disease-associated genes have been identified to date.[1,2] Mitochondrial dysfunction mainly affects organs with high energy requirements, such as the brain, central nervous system, muscle, and heart. The broad clinical and genetic presentation of mitochondrial disorders makes the molecular diagnosis challenging. Mutations can directly affect oxidative phosphorylation (OXPHOS) subunits or indirectly impair OXPHOS activity by disturbing mitochondrial homeostasis. Next-generation sequencing techniques (gene panels and exome and genome sequencing) are proving to be an appropriate tool for the diagnosis of this broad clinical group. Any diagnostic approach continues to rely upon deep
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