Mutations in the substrate binding glycine-rich loop of the mitochondria processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease

We describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia-findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for alpha-mitochondrial processing peptidase (alpha-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located dose to and postulated to affect the substrate binding glycine-rich loop of the alpha-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced alpha-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective alpha-MPP protein to a severe mitochondrial disease.