ClinVar

In 3 affected patients from 2 unrelated families (consanguineous family 1 of Moroccan origin and family 2 of Turkish origin) with mitochondrial complex V deficiency, nuclear type 7 (MC5DN7; 620359), Ganapathi et al. (2022) identified a homozygous intronic A-to-G transition (c.87+3A-G) in the ATP5PO gene, resulting in a splicing defect. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Haplotype analysis showed that the mutation arose independently in the 2 families. Studies of patient cells showed that the mutation resulted in the skipping of exon 2 and an in-frame deletion of 17 residues. Western blot analysis of patient cells showed a strong depletion of the ATP5PO protein, and enzymatic studies showed significantly decreased ATPase activity compared to controls. Assembly of the complex V holoenzyme was disrupted, and patient fibroblasts showed impaired growth and defective mitochondrial oxidative phosphorylation in a glucose-free media. Yeast studies confirmed that the mutation impaired the function of ATP5PO, causing mitochondrial respiratory defects.