The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POL?-related diseases

Mutations in the catalytic domain of mitochondrial DNA polymerase ? (POL?) cause a broad spectrum of clinical conditions. POL? mutations impair mitochondrial DNA replication, thereby causing deletions and/or depletion of mitochondrial DNA, which in turn impair biogenesis of the oxidative phosphorylation system. We here identify a patient with a homozygous p.F907I mutation in POL?, manifesting a severe clinical phenotype with develop-mental arrest and rapid loss of skills from 18 months of age. Magnetic resonance imaging of the brain revealed extensive white matter abnormalities, Southern blot of muscle mtDNA demonstrated depletion of mtDNA and the patient deceased at 23 months of age. Interestingly, the p.F907I mutation does not affect POL? activity on single-stranded DNA or its proofreading activity. Instead, the mutation affects unwinding of parental double-stranded DNA at the replication fork, impairing the ability of the POL? to support leading-strand DNA synthesis with the TWINKLE helicase. Our results thus reveal a novel pathogenic mechanism for POL?-related diseases.

Automated summary

Mutations in the catalytic domain of POL? can cause a range of clinical conditions. The p.F907I mutation in POL? leads to a severe clinical phenotype, including developmental arrest and rapid loss of skills. The mutation affects unwinding of parental double-stranded DNA at the replication fork, impairing the ability of POL? to support leading-strand DNA synthesis with the TWINKLE helicase. This study reveals a novel pathogenic mechanism for POL?-related diseases.