ClinVar

In 8 patients from 6 families with mitochondrial complex IV deficiency nuclear type 12 (MC4DN12; 619055) with a phenotype consistent with Leigh syndrome (see 256000), Lim et al. (2014) identified a homozygous c.3G-C transversion in exon 1 of the PET100 gene, predicted to abolish the translation initiation codon (met1-to-?; M1?). The mutation, which was found by homozygosity mapping combined with targeted sequencing of the candidate region, segregated with the disorder in all the families. It was not found in the dbSNP (build 132) or 1000 Genomes Project databases. Two of 81 additional Lebanese individuals who were referred for analysis of an OXPHOS defect were also found to carry the homozygous M1? mutation. All of the patients were of Lebanese descent living in Australia, and 6 of the families were consanguineous. The findings were consistent with a founder effect in this population, and the mutation was estimated to be at least 520 years old. The mutation could potentially lead to translation initiation at the next methionine at residue 10 (met10), which would yield a mutant protein, 1_9del. In vitro functional studies showed that mutant 1_9del was not imported into the mitochondria and was incapable of assembly into the 300-kD complex. The findings suggested that the N terminus is essential for mitochondrial localization. Patient fibroblasts showed a significant loss of the complex IV holoenzyme, although the subunits were translated, suggesting an assembly defect. Overexpression of the wildtype gene in patient cells restored COX2 levels and complex IV assembly.