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GLOSSARY
- ad=
- autosomal dominant;
- ANT1=
- adenine nucleotide translocator;
- ar=
- autosomal recessive;
- ATP=
- adenosine triphosphate;
- COX=
- cytochrome c oxidase;
- MELAS=
- mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes;
- MNGIE=
- mitochondrial neurogastrointestinal encephalomyopathy;
- mtDNA=
- mitochondrial DNA;
- mtSSB=
- mitochondrial single stranded binding protein;
- PEO=
- progressive external ophthalmoplegia;
- POLG=
- mitochondrial DNA polymerase γ-catalytic subunit;
- POLG=
- polymerase γ gene-catalytic subunit;
- POLG2=
- polymerase γ gene-accessory subunit;
- RHADS=
- rhythmic high-amplitude delta with superimposed spikes and polyspikes
Mitochondria are ubiquitous and play a crucial role in many vital functions, including oxidative phosphorylation and generation of adenosine triphosphate (ATP), calcium homeostasis, and apoptosis. Mitochondrial dysfunction results in neurologic and non-neurologic disorders manifesting with a broad spectrum of clinical phenotypes. In 1988, Holt and colleagues1 reported the first pathogenic mitochondrial DNA (mtDNA) mutation in mitochondrial myopathies. Since then, numerous mtDNA mutations have been identified as the cause of various disorders. Among the most prototypical of these mitochondrial disorders, linked to primary defects in the mitochondrial genome, are mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy and ragged red fibers; and neuropathy, ataxia, and retinitis pigmentosa. More than a decade after the initial reports, Van Goethem and colleagues2 discovered, in patients with progressive external ophthalmoplegia (PEO), mutations in the nuclear gene polymerase γ (POLG), which were associated with mtDNA deletions. It is now well-established that primary defects in some nuclear genes are a common cause of mitochondrial diseases and that POLG is one of those nuclear genes.3,4
POLG
Mitochondria contain their own DNA that encodes for 22 tRNA, 2 rRNA, and 13 respiratory chain protein subunits of complexes I, III, IV, and V.5 Human mtDNA is continuously replicated by DNA polymerase γ. The mtDNA polymerase γ, in combination with the mitochondrial DNA helicase Twinkle and the mitochondrial single-stranded binding protein, forms the core replication apparatus in the mitochondria (figure 1).6 The mitochondrial DNA polymerase γ is believed to be the sole polymerase responsible for mtDNA replication and repair in the mitochondria of eukaryotic cells.7 The holoenzyme is a heterotrimer consisting of a catalytic subunit and 2 smaller accessory subunits.6 The catalytic subunit (POLG) is encoded by POLG and has both polymerase and proofreading exonuclease activity resulting in high fidelity. …
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