Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain

Area of Science:

• Mitochondrial genetics
• Molecular biology
• Human genetics

Background:

• Accumulation of multiple mitochondrial DNA (mtDNA) deletions in stable tissues is a poorly understood pathological mechanism.
• Progressive external ophthalmoplegia (PEO) and mitochondrial neurogastrointestinal encephalomyopathy are debilitating conditions linked to mtDNA instability.

Purpose of the Study:

• To elucidate the pathological mechanisms underlying the accumulation of multiple mtDNA deletions in stable tissues.
• To investigate the role of specific gene mutations in mtDNA integrity.

Main Methods:

• Large-scale screening of mtDNA molecules from skeletal muscle in patients with PEO and mitochondrial neurogastrointestinal encephalomyopathy.
• Analysis of mutations in ANT1, C10ORF2, POLG1, and TP genes.
• Assessment of mtDNA mutational burden in fibroblasts from patients with PEO.

Main Results:

• Mutations in the exonuclease domain of POLG1 correlated with a higher frequency of rare point mutations in the mtDNA control region.
• Recurrent mutations (A189G, T408A, T414G) and alterations in the (HT)D310 region were frequently detected in patients.
• Homozygous POLG1 mutations in the exonuclease domain increased the mutational burden in patient fibroblasts.

Conclusions:

• Specific POLG1 mutations compromise mtDNA integrity by reducing proof-reading exonuclease activity.
• This reduction in activity leads to the accumulation of heteroplasmic levels of both rare and recurrent mtDNA point mutations.
• The findings implicate POLG1 mutations as a direct cause of mtDNA instability in skeletal muscle and fibroblasts.