title: A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability.
abstract: Complex III (cytochrome bc1) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c. Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83, hereafter named UQCC3, to be the ortholog of the fungal complex III assembly factor CBP4. We describe a homozygous c.59T>A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T>A mutation has a causal role in complex III deficiency.
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Bas F J
authors.initials: BF
authors.lastname: Wanschers
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, 6200MD Maastricht, The Netherlands.
authors.forename: Radek
authors.initials: R
authors.lastname: Szklarczyk
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Mariël A M
authors.initials: MA
authors.lastname: van den Brand
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: An
authors.initials: A
authors.lastname: Jonckheere
authors.affiliation: Laboratory of Genetic, Endocrine, and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen,The Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Suijskens
authors.affiliation: Laboratory of Genetic, Endocrine, and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen,The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Smeets
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, Stockholm SE-106 91, Sweden.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stephan
authors.affiliation: Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Helland
authors.affiliation: Department of Pediatrics, St Olav's University Hospital, Trondheim 7006, Norway.
authors.forename: Areej
authors.initials: A
authors.lastname: Elkamil
authors.affiliation: Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway, University of Oslo, Oslo 0424, Norway and.
authors.forename: Terje
authors.initials: T
authors.lastname: Rootwelt
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, Stockholm SE-106 91, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ott
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, Laboratory of Genetic, Endocrine, and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen,The Netherlands, Department of Pediatrics, Catholic University Leuven, Leuven 3000, Belgium.
authors.forename: Lambert
authors.initials: L
authors.lastname: van den Heuvel
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, huynen@cmbi.ru.nl.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003241:Consanguinity; D045303:Cytochromes b / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D045303:Cytochromes b; D014450:Electron Transport Complex III; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; C088917:CBP4 protein, S cerevisiae; C546538:UQCC2 protein, human; C582875:UQCC1 protein, human; C000597855:UQCC3 protein, human