Clinical and Molecular Features of POLG-Related Mitochondrial Disease

The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.While many polymerases are responsible for replicating billions of nucleotides in the nucleus, DNA polymerase γ replicates thousands of copies of the 16-kilobase mitochondrial genome (mtDNA) in each human cell. The holoenzyme of DNA polymerase γ (pol γ) consists of a catalytic subunit (encoded by POLG at chromosomal locus 15q25) and a dimeric form of its accessory subunit (encoded by POLG2 at chromosomal locus 17q24.1) (Longley et al. 1998b; Lim et al. 1999). MtDNA encodes 13 proteins that are essential for the electron transport chain that provides most of the ATP in the cell. Therefore, mtDNA replication is essential for life as demonstrated by the embryonic lethality of POLG knockout mice (Hance et al. 2005). Studies over the last decade have identified over 200 mutations in POLG that are associated with certain mitochondrial diseases (http://tools.niehs.nih.gov/polg/) (Longley et al. 2005: Copeland 2008; Longley et al. 2010; Walter et al. 2010; Stumpf and Copeland 2011; Tang et al. 2011). POLG-related disorders are currently defined by at least five major phenotypes of neurodegenerative disease that include: (1) Alpers-Huttenlocher syndrome (AHS), (2) childhood myocerebrohepatopathy spectrum (MCHS), (3) myoclonic epilepsy myopathy sensory ataxia (MEMSA), (4) the ataxia neuropathy spectrum (ANS), and (5) progressive external ophthalmoplegia (PEO) with or without sensory ataxic neuropathy and dysarthria (SANDO) (Wong et al. 2008; Cohen et al. 2010; Saneto and Naviaux 2010; Saneto et al. 2010). These diseases associate with mutations that have been shown to decrease the activity of the polymerase, the fidelity of replication, and the formation of the holoenzyme. This work reviews the important conclusions regarding POLG-related diseases and discusses some strategies for disease treatment options.