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Case Reports
. 2016 Dec;53(12):846-849.
doi: 10.1136/jmedgenet-2016-104194. Epub 2016 Sep 28.

COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency

Anabel Martinez Lyons  1 , Anna Ardissone  2 , Aurelio Reyes  1 , Alan J Robinson  1 , Isabella Moroni  2 , Daniele Ghezzi  3 , Erika Fernandez-Vizarra  1 , Massimo Zeviani  1
Affiliations
Case Reports

COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency

Anabel Martinez Lyons et al. J Med Genet. 2016 Dec.

Abstract

Background: Assembly of cytochrome c oxidase (COX, complex IV, cIV), the terminal component of the mitochondrial respiratory chain, is assisted by several factors, most of which are conserved from yeast to humans. However, some of them, including COA7, are found in humans but not in yeast. COA7 is a 231aa-long mitochondrial protein present in animals, containing five Sel1-like tetratricopeptide repeat sequences, which are likely to interact with partner proteins.

Methods: Whole exome sequencing was carried out on a 19 year old woman, affected by early onset, progressive severe ataxia and peripheral neuropathy, mild cognitive impairment and a cavitating leukodystrophy of the brain with spinal cord hypotrophy. Biochemical analysis of the mitochondrial respiratory chain revealed the presence of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts and skeletal muscle. Mitochondrial localization studies were carried out in isolated mitochondria and mitoplasts from immortalized control human fibroblasts.

Results: We found compound heterozygous mutations in COA7: a paternal c.410A>G, p.Y137C, and a maternal c.287+1G>T variants. Lentiviral-mediated expression of recombinant wild-type COA7 cDNA in the patient fibroblasts led to the recovery of the defect in COX activity and restoration of normal COX amount. In mitochondrial localization experiments, COA7 behaved as the soluble matrix protein Citrate Synthase.

Conclusions: We report here the first patient carrying pathogenic mutations of COA7, causative of isolated COX deficiency and progressive neurological impairment. We also show that COA7 is a soluble protein localized to the matrix, rather than in the intermembrane space as previously suggested.

Keywords: COX assembly; Molecular genetics; Neurology; mitochondrial disease; mitochondrial respiratory chaixn.

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Conflict of interest statement

Conflicts of Interest: None declared.

Figures

Figure 1
Figure 1
Clinical and genetic findings. (A) Transverse supratentorial (i), coronal (ii) and sagittal brain/spinal cord (iii) T2- fluid attenuated inversion recovery (FLAIR) MRI sequences. (B) Sanger sequence of the mutated regions in cDNA from mutant fibroblasts. (C) Clustal W diagram. Boxed areas correspond to mutations. Sel1-like conserved domains are underlined.
Figure 2
Figure 2
Western blot (WB) immunodetection and enzymatic activities. (A) WB immunodetection of SDS-PAGE in primary fibroblasts. P, patient, C1 and C2, control cell lines. (B) WB immunodetection of BNGE in immortalised patient (Pi) and control (C3i) fibroblasts. Immunovisualised subunits are between brackets. (C) WB immunodetection of SDS-PAGE in immortalised patient fibroblasts (Pi) and a control (C4i). n.t., not transduced; mock, transduced with empty vector; COA7, transduced with COA7. (D) WB immunodetection of BNGE in COA7-transduced immortalised fibroblasts from patient (Pi) and a control (C4i). (E) Cytochrome c oxidase (COX)/citrate synthase (CS) activity in immortalised fibroblasts of two controls (C3i, C4i), and the patient (Pi). Vertical bars indicate SEM. Statistical analysis was by ANOVA (*p<0.05; **p<0.01; ***p<0.001). (F) WB immunodetection of SDS-PAGE of mitochondria and mitoplasts from HEK293T cells. (G) WB immunodetection of SDS-PAGE of soluble and membrane fractions from intact mitochondria. ANOVA, analysis of variance.
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