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Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1
Journal article   Open access   Peer reviewed

Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1

Silvio Ferraris, Susanna Clark, Emanuela Garelli, Guido Davidzon, Steven A Moore, Randy H Kardon, Rachelle J Bienstock, Matthew J Longley, Michelangelo Mancuso, Purificación Gutiérrez Ríos, …
Archives of neurology (Chicago), Vol.65(1), pp.125-131
01/2008
DOI: 10.1001/archneurol.2007.9
PMCID: PMC2364721
PMID: 18195150
url
https://doi.org/10.1001/archneurol.2007.9View
Published (Version of record) Open Access

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 gamma (POLG2) and a mutation in the OPA1 gene. Clinical examination and morphological, biochemical, and molecular analyses. Tertiary care university hospitals and molecular genetics and scientific computing laboratory. 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. 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 gamma 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). 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.
 Immunohistochemistry DNA Polymerase gamma Blotting, Southern Hearing Loss - etiology Lactic Acid - blood Humans Male DNA-Directed DNA Polymerase - genetics Mutation, Missense - genetics Oncogene Protein p55(v-myc) - genetics DNA, Mitochondrial - genetics Adult Ataxia - genetics Muscle, Skeletal - enzymology Cytochromes c - metabolism Dynamins - genetics Models, Molecular Reverse Transcriptase Polymerase Chain Reaction Anemia, Macrocytic - complications Hearing Loss - genetics Hypogonadism - genetics Vision Disorders - genetics Biopsy GTP Phosphohydrolases - genetics Hypogonadism - complications Muscle Fibers, Skeletal - pathology Succinate Dehydrogenase - metabolism Ataxia - complications Ophthalmoplegia - complications Ophthalmoplegia - genetics Muscle, Skeletal - pathology Anemia, Macrocytic - genetics Vision Disorders - etiology

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