DNA polymerase γ (pol γ), encoded by POLG, is responsible for replicating human 
mitochondrial DNA. About 150 mutations in the human POLG have been identified in 
patients with mitochondrial diseases such as Alpers syndrome, progressive 
external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the 
mutations are described in single citations with no genotypic family history, it 
is important to ascertain which mutations cause or contribute to mitochondrial 
disease. The vast majority of data about POLG mutations has been generated from 
biochemical characterizations of recombinant pol γ. However, recently, the study 
of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models 
provides important in vivo evidence for the role of POLG mutations in disease. 
Also, the published 3D-structure of the human pol γ assists in explaining some 
of the biochemical and genetic properties of the mutants. This review summarizes 
the current evidence that identifies and explains disease-causing POLG 
mutations.