title: Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
abstract: Isolated cytochrome c oxidase (complex IV) deficiency is one of the most frequent respiratory chain defects in humans and is usually caused by mutations in proteins required for assembly of the complex. Mutations in nuclear-encoded structural subunits are very rare. In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy, we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV. The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript. The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts, similar to the frequent c.845_846delCT mutation in the assembly factor SURF1 gene. Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A. Our findings demonstrate that COX8A is indispensable for function of human complex IV and its mutation causes human disease.
authors.affiliation: 1 Department of Epileptology and Life and Brain Centre, University of Bonn, Bonn, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hallmann
authors.affiliation: 1 Department of Epileptology and Life and Brain Centre, University of Bonn, Bonn, Germany.
authors.forename: Alexei P
authors.initials: AP
authors.lastname: Kudin
authors.affiliation: 1 Department of Epileptology and Life and Brain Centre, University of Bonn, Bonn, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Zsurka
authors.affiliation: 2 Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kornblum
authors.affiliation: 2 Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Reimann
authors.affiliation: 3 Children's Hospital Cologne, Cologne, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Stüve
authors.affiliation: 3 Children's Hospital Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Waltz
authors.affiliation: 4 Department of Radiology, Division of Neuroradiology, University of Bonn, Bonn, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
authors.affiliation: 5 Cologne Centre for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: 5 Cologne Centre for Genomics (CCG), University of Cologne, Cologne, Germany 6 Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany 7 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 8 Institut für Biochemie und Molekularbiologie, University of Bonn, Bonn, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rüb
authors.affiliation: 8 Institut für Biochemie und Molekularbiologie, University of Bonn, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Voos
authors.affiliation: 9 Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Kopatz
authors.affiliation: 9 Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
authors.affiliation: 1 Department of Epileptology and Life and Brain Centre, University of Bonn, Bonn, Germany wolfram.kunz@ukb.uni-bonn.de.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
mesh_terms: D002648:Child; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000502:physiology; D004827:Epilepsy / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007888:Leigh Disease / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*
chemical_list: D021122:Protein Subunits; C477826:COX8C protein, human; D003576:Electron Transport Complex IV
keywords: Leigh-like syndrome; cytochrome c oxidase; mitochondrial disease; subunit COX VIIIa