Clinical and Molecular Features of <em>POLG</em>-Related Mitochondrial Disease

Abstract

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.

^{Adapted from Haas et al. (2007, 2008) and Cohen and Naviaux (2010).}

^{Table data adapted from Saneto and Naviaux (2010).}

^{ANS has also been labeled as mitochondrial recessive ataxia syndrome (MIRAS), sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO), and spino-cerebellar ataxia epilepsy syndrome (SCAE) (Tzoulis et al. 2006).}

^{PEO is labeled as PEO+ when associated with additional symptoms that may include peripheral neuropathy, ataxia, hearing loss, depression, premature menopause, hypogonadism, Parkinsonism, cataracts, or GI dysmotility.}

^{Dominant and recessive mutations in} POLG have been associated with PEO.

NA, not applicable (because there is no homolog in yeast); ANS, ataxia neuropathy syndromes.

ACKNOWLEDGMENTS

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