Progressive External Ophthalmoplegia and Vision and Hearing Loss in a Patient With Mutations in POLG2 and OPA1

Abstract

To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase ␥ (POLG2) and a mutation in the OPA1 gene.Design: Clinical examination and morphological, biochemical, and molecular analyses.Setting: Tertiary care university hospitals and molecular genetics and scientific computing laboratory.Patient: A 42-year-old man experienced hearing loss, progressive external ophthalmoplegia (PEO), loss of central vision, macrocytic anemia, and hypogonadism. His family history was negative for neurological disease, and his serum lactate level was normal.Results: A muscle biopsy specimen showed scattered intensely succinate dehydrogenase-positive and cytochrome-c oxidase-negative fibers. Southern blot of muscle mitochondrial DNA showed multiple deletions. The results of screening for mutations in the nuclear genes associated with PEO and multiple mitochondrial DNA deletions, including those in POLG (polymerase ␥ gene), ANT1 (gene encoding adenine nucleotide translocator 1), and PEO1, were negative, but sequencing of POLG2 revealed a G1247C mutation in exon 7, resulting in the substitution of a highly conserved glycine with an alanine at codon 416 (G416A). Because biochemical analysis of the mutant protein showed no alteration in chromatographic properties and normal ability to protect the catalytic subunit from N-ethylmaleimide, we also sequenced the OPA1 gene and identified a novel heterozygous mutation (Y582C). Conclusion:Although we initially focused on the mutation in POLG2, the mutation in OPA1 is more likely to explain the late-onset PEO and multisystem disorder in this patient.

Novel Twinkle (PEO1) gene mutations in mendelian progressive external ophthalmoplegia

“…A heterozygous dominant mutation in POLG2 was also shown to cause PEO [2]. Mutations in OPA1 gene are also emerging as a new cause of autosomal dominant "optic atrophy plus" phenotype with muscle accumulation of multiple mtDNA deletions [5][6][7]. Although the involvement of this gene in patients without optic nerve atrophy as a prominent clinical feature cannot be excluded at this moment, the absence of optic neuropathy in the undiagnosed patients of the present study makes this hypothesis unlikely.…”

“…They include POLG1 that encodes the catalytic subunit of DNA polymerase γ (pol γ) [1], POLG2 encoding the p55 accessory polγ subunit [2], ANT1 coding for the mitochondrial adenine nucleotide translocator [3], and PEO1 (formerly C10ORF2) which codes for Twinkle, a mitochondrial protein with structural similarity to the phage T7 primase/ helicase [4]. Heterozygous missense mutations in the OPA1 gene leading to accumulation of mtDNA deletions in muscle tissue have been observed in families with optic atrophy, PEO and other variable signs such as ataxia, deafness and a sensory-motor neuropathy [5][6][7].…”

Progressive External Ophthalmoplegia in Southwestern Finland: A Clinical and Genetic Study

“…ANT1 and PEO1 genes were sequenced and analyzed for mutations as described elsewhere [11,12] . The POLG2 gene was analyzed as described elsewhere [29] , with minor improvements to cover the whole coding region of the gene.…”

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.…”