Polymerase gamma disease through the ages

Abstract

The most common group of mitochondrial disease is due to mutations 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 demonstrate 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: exonuclease, linker, and polymerase domains. Most of the mutations leading to dominant forms of POLG disease are located in the Polymerase domain. 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 pharmacogenetic 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 identify genotype-phenotype relationships, give clues for diagnosis, and summarize the major clinical phenotypes in the spectrum of POLG disease presenting from birth to old age.

Status epilepticus caused by an unusual encephalopathy

“…The carrier frequency of the most common mutation, A467T, is as high as 1% in some European populations 2. The first pathogenic mutation was found in 2001,3 but since then over 150 have been described 4…”

Mitochondrial DNA maintenance: an appraisal

“…[129] Albeit not all these mutations have been characterized biochemically, there is increasing evidence that they may contribute to disease pathogenesis. These rare hereditary mitochondrial diseases include neurodegenerative disorders, such as mtDNA depletion syndromes (e.g., Alpers-Huttenlocher or early childhood hepatocerebral syndromes) and mtDNA deletion disorders (e.g., ataxia neuropathy, autosomal recessive PEO [arPEO], and autosomal dominant PEO [adPEO]) (http://www.genetests.org) [250,252,253]. The number of patients affected with recessive pathogenic b Fig.…”

Evaluation of the Child With Suspected Mitochondrial Liver Disease

“…Most common with liver involvement: POLG1 (15,16), DGUOK (17)(18)(19), MPV17 (20,21) , SUCLG1 (22), C10ORF2/Twinkle (23), TRMU (see Tables 3 and 4 For recurrent acute liver failure: TRMU, ACAD9, CPTI, SUCLGI. (22,26,30,31) Identification of TRMU mutations is urgent in infants with acute liver failure since these patients frequently recover without the need for transplantation.…”