POLYMERASE GAMMA DISEASE THROUGH THE AGES Russell P. Saneto 1 * and Robert K. Naviaux 2,3 1 Division of Pediatric Neurology, Seattle Children’s Hospital/University of Washington, Seattle, Washington 2 Department of Medicine, University of California San Diego, California 3 Department of Pediatrics, University of California San Diego, California The most common group of mitochondrial disease is due to muta- tions within the mitochondrial DNA polymerase, polymerase gamma 1 (POLG). This gene product is responsible for replication and repair of the small mitochondrial DNA genome. The structure-function relationship of this gene product produces a wide variety of diseases that at times, seems to defy the common perceptions of genetics. The unique features of mitochondrial physiology are in part responsible, but POLG structure and function add to the conundrum of how one gene product can dem- onstrate autosomal recessive and autosomal dominant transmission, while also being responsible for pharmacogenetic disease, and exhibiting strong gene-environment interactions. The wide spectrum of clinical manifestations of POLG disease can arise from infancy to old age. The modulation of clinical findings relate in part to the molecular architecture of the POLG protein. POLG has three distinct molecular domains: exonu- clease, linker, and polymerase domains. Most of the mutations leading to dominant forms of POLG disease are located in the Polymerase do- main. Mutations leading to recessive inheritance are distributed in all three domains of the gene. Environmental factors like valproic acid and infection can unmask POLG disease, causing it to occur earlier in life than when not exposed to these factors. Other drugs like nucleoside reverse transcriptase inhibitors can produce genotype-specific POLG pharmacoge- netic disease. Our current state of POLG understanding cannot account for many features of POLG disease. There is no answer for why the same mutation can give rise to varying diseases, disease severity, and age of onset. We introduce the term Ecogenetics in the context these features of POLG disease, to emphasize the important interactions between genes and environment in determining the expression of mitochondrial disease. In this article, we identify some of the key features that will help the reader understand POLG pathophysiology. When possible, we also iden- tify genotype-phenotype relationships, give clues for diagnosis, and sum- marize the major clinical phenotypes in the spectrum of POLG disease presenting from birth to old age. ' 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:163–174. Key Words: polymerase gamma; mitochondrial disease; gene mutation; DNA; genetic inheritance; POLG spectrum disorders T he unique physiology of mitochondria has created new paradigms of genetic inheritance and genotype-pheno- type relationships in disease. The semiautonomous na- ture of this organelle has created a ‘‘puzzle wrapped in an enigma’’ in the diversity of human disease. The center piece of this puzzle is the gene coding for the mitochondrial DNA (mtDNA) polymerase, polymerase gamma 1 (MIM# 174763, POLG). Mitochondria contain their own small 16.5 kilobase (kb) circular double-stranded DNA genome that codes for 13 poly- peptides, as well as the necessary tRNAs and rRNAs for their synthesis. These 13 protein subunits combine with over 70 proteins that are coded by nuclear genes to be assembled to- gether within the mitochondria to form the electron transport chain, which is the final conduit for energy production [Smei- tink et al., 2001; DiMauro and Schon, 2003]. Ultimately, all mitochondrial disease results either from disordered produc- tion of energy in the form of adenosine triphosphate (ATP), or from defects in other key mitochondrial functions like cal- cium homeostasis, apoptosis, and innate immunity. Initially, it was thought that mutations within the mtDNA were the major cause of human disease [Thorburn and Dahl, 2000; Schaefer et al., 2004]. However, within the last several years a new class of mitochondrial disease has arisen: disorders of nu- clear-mitochondrial intergenomic cross talk [Spinazzola and Zeviani, 2009], which is becoming the most common form of mitochondrial disease [Chinnery and Zeviani, 2008]. The major participant in both replication and maintenance of mtDNA is POLG. POLG is transcribed in the cell nucleus, translated in the cytosol, and then transported across the outer and inner mitochondrial membranes to the inner face of the inner mito- chondrial membrane where it associates with other proteins that make up the mtDNA replisome and nucleoids within the organelle. It is believed to be the only DNA polymerase within the mitochondrion of animal cells [Kaguini, 2004]. Mutations within POLG can produce a variety of genetic defects within the mtDNA [reviewed in Copeland, 2008]. Indeed, in mutations within the nuclear-encoded POLG gene induce mutations within mitochondrial DNA itself, causing mtDNA copy number depletion, base pair substitutions, and multiple base pair deletions that result in a variety of disease *Correspondence to: Russell P. Saneto, DO, PhD, Associate Professor of Neurology and Pediatrics, Seattle Children Hospital/University of Washington, Mail Stop B-5552, 4800 Sand Point Way NE, Seattle, WA 98105. E-mail: russ.saneto@seattlechildrens.org Received 21 May 2010; Accepted 1 July 2010 View this article online at wileyonlinelibrary.com. DOI: 10.1002/ddrr.105 DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 16: 163 – 174 (2010) ' 2010 Wiley -Liss, Inc.