PT - JOURNAL ARTICLE AU - Anabel Martinez Lyons AU - Anna Ardissone AU - Aurelio Reyes AU - Alan J Robinson AU - Isabella Moroni AU - Daniele Ghezzi AU - Erika Fernandez-Vizarra AU - Massimo Zeviani TI - <em>COA7</em> (<em>C1orf163</em><em>/RESA1</em>) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency AID - 10.1136/jmedgenet-2016-104194 DP - 2016 Dec 01 TA - Journal of Medical Genetics PG - 846--849 VI - 53 IP - 12 4099 - http://jmg.bmj.com/content/53/12/846.short 4100 - http://jmg.bmj.com/content/53/12/846.full SO - J Med Genet2016 Dec 01; 53 AB - 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&gt;G, p.Y137C, and a maternal c.287+1G&gt;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.