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



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.



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.



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.
MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.
Anabel
A
Martinez Lyons
Department of Child Neurology, Milan, Italy.
Anna
A
Ardissone
MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.
Aurelio
A
Reyes
MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.
Alan J
AJ
Robinson
Department of Child Neurology, Milan, Italy.
Isabella
I
Moroni
Unit of Molecular Neurogenetics of the Fondazione Istituto Neurologico "Carlo Besta", Milan, Italy.
Daniele
0000-0002-6564-3766
D
Ghezzi
MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.
Erika
E
Fernandez-Vizarra
MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.
Massimo
M
Zeviani
D000595:Amino Acid Sequence; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D016415:Sequence Alignment; D055815:Young Adult
C000588697:COA7 protein, human; D024101:Mitochondrial Proteins
COX assembly; Molecular genetics; Neurology; mitochondrial disease; mitochondrial respiratory chaixn
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