Case Report/Case Series |

COX10 Mutations Resulting in Complex Multisystem Mitochondrial Disease That Remains Stable Into Adulthood

Robert D. S. Pitceathly, MRCP1; Jan-Willem Taanman, PhD2; Shamima Rahman, PhD1,3; Brigitte Meunier, PhD4; Michael Sadowski, PhD5; Sebahattin Cirak, PhD6; Iain Hargreaves, PhD7; John M. Land, PhD7; Tina Nanji, BSc8; James M. Polke, PhD8; Cathy E. Woodward, BSc8; Mary G. Sweeney, BSc8; Shyam Solanki, BSc2; A. Reghan Foley, MD6; Matthew E. Hurles, PhD9; Jim Stalker, MA9; Julian Blake, MRCP10,11; Janice L. Holton, PhD1,12; Rahul Phadke, FRCPath6,12; Francesco Muntoni, MD6; Mary M. Reilly, FRCP1,13; Michael G. Hanna, FRCP1,13; for the UK10K Consortium
[+] Author Affiliations
1Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England
2Department of Clinical Neuroscience, University College London Institute of Neurology, London, England
3Mitochondrial Research Group, Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London, England
4Centre de Génétique Moléculaire, UPR3404, Centre national de la recherche scientifique, Gif-sur-Yvette, France
5Division of Mathematical Biology, National Institute for Medical Research, London, England
6Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, England
7Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, England
8Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, England
9The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, England
10Department of Clinical Neurophysiology, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England
11Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, England
12Division of Neuropathology, University College London Institute of Neurology, London, England
13Department of Molecular Neuroscience, University College London Institute of Neurology, London, England
JAMA Neurol. 2013;70(12):1556-1561. doi:10.1001/jamaneurol.2013.3242.
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Importance  Isolated cytochrome-c oxidase (COX) deficiency is one of the most frequent respiratory chain defects seen in human mitochondrial disease. Typically, patients present with severe neonatal multisystem disease and have an early fatal outcome. We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.

Observations  Whole-exome sequencing detected 1 known pathogenic and 1 novel COX10 mutation: c.1007A>T; p.Asp336Val, previously associated with fatal infantile COX deficiency, and c.1015C>T; p.Arg339Trp. Muscle COX holoenzyme and subassemblies were undetectable on immunoblots of blue-native gels, whereas denaturing gels and immunocytochemistry showed reduced core subunit MTCO1. Heme absorption spectra revealed low heme aa3 compatible with heme A:farnesyltransferase deficiency due to COX10 dysfunction. Both mutations demonstrated respiratory deficiency in yeast, confirming pathogenicity. A COX10 protein model was used to predict the structural consequences of the novel Arg339Trp and all previously reported substitutions.

Conclusions and Relevance  These findings establish that COX10 mutations cause adult mitochondrial disease. Nuclear modifiers, epigenetic phenomenon, and/or environmental factors may influence the disease phenotype caused by reduced COX activity and contribute to the variable clinical severity related to COX10 dysfunction.

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Figure 1.
Results of Sural Nerve Biopsy, Electron Microscopy, and Muscle Biopsy

A, Sural nerve biopsy specimen. High-magnification view of one fascicle (semithin section of resin stained with methylene blue-azure basic fuchsin) shows moderate depletion of myelinated fibers with several large diameter axonal profiles displaying inappropriately thin myelin sheaths for their diameter, suggesting demyelination (A [arrowheads]). Electron microscopy demonstrates 2 examples of demyelinating axons (B and C) and tightly packed inclusions within a myelinated fiber Schwann cell cytoplasm (D [asterisk]). E, Inspection at higher magnification shows membrane-bound filamentous inclusions (asterisks) closely associated with the Golgi cisternae (arrowheads). F, Muscle biopsy specimen shows decreased COX staining in the majority of fibers. Ragged-red fibers were not present. Scale bars represent 100 μm.

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Figure 2.
Immunoblot Analysis, Immunocytochemical Micrographs, and Muscle Heme Absorption Spectra

Immunoblot analysis of blue-native (A) and sodium dodecyl sulfate (B) polyacrylamide gels loaded with mitochondrial membrane proteins extracted from muscle. A, The cytochrome-c oxidase (COX) holoenzyme was undetectable in the patient (P), unlike the controls (C1-3). B, The COX10 protein steady state levels were normal in the patient compared with the controls, indicating that the COX10 missense mutations do not impair COX10 protein stability, whereas MTCO1 was undetectable in the patient, unlike the controls. C, Micrographs of a control’s and the patient’s fibroblasts are shown immunocytochemically stained for MTCO1 (green fluorescence) and MitoTracker Red (Life Technologies; red fluorescence), and counterstained with the DNA fluorochrome 4′,6-diamidino-2-phenylindole (blue fluorescence); the patient’s cells show a general decrease in MTCO1 levels compared with the control’s cells. D, Air-oxidized vs sodium dithionite–reduced heme spectra of the patient’s muscle mitochondrial proteins are shown. There is loss of the heme aa3 γ band at 445 nm (D [arrowhead]) in the patient compared with the control. MW indicates molecular weight.

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Figure 3.
Growth of Yeast on a Nonfermentable Carbon Source and Hypothetical COX10 Protein Model

Growth of COX10 p.Asp336Val, COX10 p.Arg339Trp and COX10 Asp336Val plus Arg339Trp yeast strains and a control on glucose (A) and glycerol/ethanol (B) as carbon source. Both COX10 mutations cause respiratory deficiency, as demonstrated by the impaired growth on the nonfermentable carbon source glycerol/ethanol. When both mutations coexisted, the respiratory deficiency appeared to be even more pronounced (A and B). C, A topology diagram of the COX10 protein shows locations of both known and the herein reported mutated COX10 residues highlighted in red; the transmembrane segments are labeled with Roman numerals (I-IX). A structural model of COX10 shows the locations of residues 336, 339, and 225 (D) and residues 196, 204, 225, 336, and 339 looking up from the mitochondrial matrix at the putative face of the bundle (E). COOH indicates the C-terminus (also known as the carboxyl terminus) of the protein; and H2N, the N-terminus (also known as the amino terminus) of the protein.

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