2. Academic Validation
  3. Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy

Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy

  • Brain. 2016 Feb;139(Pt 2):338-45. doi: 10.1093/brain/awv357.
Kerstin Hallmann 1,  Alexei P Kudin 1,  Gábor Zsurka 1,  Cornelia Kornblum 2,  Jens Reimann 2,  Burkhard Stüve 3,  Stephan Waltz 3,  Elke Hattingen 4,  Holger Thiele 5,  Peter Nürnberg 6,  Cornelia Rüb 7,  Wolfgang Voos 7,  Jens Kopatz 8,  Harald Neumann 8,  Wolfram S Kunz 9
Affiliations

Affiliations

  • 1 1 Department of Epileptology and Life and Brain Centre, University of Bonn, Bonn, Germany.
  • 2 2 Department of Neurology, University of Bonn, Bonn, Germany.
  • 3 3 Children's Hospital Cologne, Cologne, Germany.
  • 4 4 Department of Radiology, Division of Neuroradiology, University of Bonn, Bonn, Germany.
  • 5 5 Cologne Centre for Genomics (CCG), University of Cologne, Cologne, Germany.
  • 6 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.
  • 7 8 Institut für Biochemie und Molekularbiologie, University of Bonn, Bonn, Germany.
  • 8 9 Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany.
  • 9 1 Department of Epileptology and Life and Brain Centre, University of Bonn, Bonn, Germany [email protected].
PMID: 26685157 DOI: 10.1093/brain/awv357
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.

Keywords

Leigh-like syndrome; cytochrome c oxidase; mitochondrial disease; subunit COX VIIIa.

Figures