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Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome
  1. C E Oquendo1,
  2. H Antonicka2,
  3. E A Shoubridge2,
  4. W Reardon3,
  5. G K Brown1
  1. 1Genetics Unit, Department of Biochemistry, University of Oxford, UK
  2. 2Department of Human Genetics, McGill University, Montreal, Canada
  3. 3Our Lady’s Hospital for Sick Children, Dublin, Ireland
  1. Correspondence to:
 Dr G K Brown
 Genetics Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK; garry.brownbioch.ox.ac.uk

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Leigh syndrome is a subacute necrotising encephalomyelopathy characterised by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs. The main laboratory findings are raised lactate in the blood and cerebrospinal fluid, but the diagnosis is only confirmed by the presence of bilateral symmetrical lesions in the basal ganglia, thalamus, brain stem, and cerebellum. Leigh syndrome can result from a number of different defects in mitochondrial energy metabolism, most commonly deficiencies of cytochrome oxidase (COX), pyruvate dehydrogenase, NADH-ubiquinone oxidoreductase (Complex I) and ATP synthase.1 In patients with Leigh syndrome and cytochrome oxidase deficiency, the underlying genetic defect is usually a mutation in the SURF1 gene, which maps to chromosome 9q34 and encodes a cytochrome oxidase assembly factor.2,3 In a small number of cases, Leigh syndrome and cytochrome oxidase deficiency have been found in patients with mutations in mitochondrial DNA (mtDNA)4,5 and in one patient with mutations in the COX10 gene.6

Cytochrome oxidase is the terminal complex of the electron transport chain. It transfers electrons from cytochrome c to molecular oxygen and contributes to the proton motive force used in the generation of ATP. The mammalian complex is composed of thirteen subunits, three encoded in mtDNA and ten in nuclear DNA.7 Some of the nuclear subunits have different isoforms, which are coded by multigene families and are expressed in different tissues and at different stages of development.8–14 The cytochrome oxidase complex contains four prosthetic groups, haeme a, haeme a3, CuA and CuB, which are essential for the redox reaction. Therefore, generation of a fully functional complex in the inner mitochondrial membrane requires: (a) transcription and translation of 13 proteins in two different compartments of the cell, (b) correct assembly in …

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