Late-onset ptosis and myopathy in a patient with a heterozygous insertion in POLG2

Abstract

Polymerase gamma 1 (POLG) mutations are a frequent cause of both autosomal dominant and recessive complex neurological phenotypes. In contrast, only a single pathogenic mutation in one patient was reported in POLG2 so far. Here we describe a 62-year-old woman, carrying a novel heterozygous sequence variant in the POLG2 gene. She developed bilateral ptosis at 30 years of age, followed by exercise intolerance, muscle weakness and mild CK increase in her late forties. Muscle histology and respiratory chain activities were normal. Southern blot and long range PCR detected multiple mtDNA deletions, but no depletion in muscle DNA. Sequencing of POLG, PEO1, ANT1, OPA1 and RRM2B showed normal results. A novel heteroallelic 24 bp insertion (c.1207_1208ins24) was detected in POLG2. This 24 bp insertion into exon 7 causes missplicing and loss of exon 7 in myoblast cDNA. We did not detect POLG2 mutations in 62 patients with multiple mtDNA deletions in muscle DNA, suggesting that POLG2 mutations may represent a rare cause of autosomal dominant PEO.

Yeast Cells Expressing the Human Mitochondrial DNA Polymerase Reveal Correlations between Polymerase Fidelity and Human Disease Progression

“…In particular, yeast does not encode the homolog of accessory subunit of Pol-␥ (Pol-␥B), and the accessory interaction domain is not conserved in yeast. Several pathogenic point mutations are found in these domains (30,31) in humans and cannot be tested using MIP1. Thus, despite evolutionary relationships between yeast and humans, one might question whether the human mtDNA polymerase could provide functional substitution for the yeast polymerase.…”

Clinical and Molecular Features of POLG-Related Mitochondrial Disease

“…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 2008Longley 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 myocerebrohepatopathyspectrum (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) ).…”

Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion

“…Nearly 250 pathogenic POLG mutations have been reported [Copeland 2014] and these are associated with clinical phenotypes ranging from mild adult-onset CPEO to rapidly fatal Alpers-Huttenlocher syndrome characterized by myopathy, hepatopathy and intractable seizures. In contrast to POLG , to date, only two heterozygous mutations of POLG2 have been described, and these are associated with late-onset autosomal dominant PEO with multiple mtDNA deletions (OMIM 610131) [Longley and others 2006; Walter and others 2010; Young and others 2011]. POLG2 encodes the accessory subunit of DNA polymerase γ, and is required for imparting high processivity to POLG by increasing the affinity of the protein complex to DNA [Lim and others 1999].…”

“…Mutations in POLG are a common cause of MDS, and lead to broad and variable phenotypes including progressive external ophthalmoplegia (PEO) with both autosomal dominant and recessive inheritance, myopathy, neurological and hepatocerebral forms [Copeland 2014]. In contrast to POLG mutations, only rare cases of heterozygous mutations in POLG2 causing mtDNA depletion have been described in association with autosomal dominant PEO and muscle weakness (MIM 610131, PEOA4) [Longley and others 2006; Walter and others 2010; Young and others 2011]. …”