title: Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Clinical examination and morphological, biochemical, and molecular analyses.
  
  
  METHODS
  Tertiary care university hospitals and molecular genetics and scientific computing laboratory.
  
  
  METHODS
  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 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, University of Turin, Turin, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Ferraris
authors.forename: Susanna
authors.initials: S
authors.lastname: Clark
authors.forename: Emanuela
authors.initials: E
authors.lastname: Garelli
authors.forename: Guido
authors.initials: G
authors.lastname: Davidzon
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Randy H
authors.initials: RH
authors.lastname: Kardon
authors.forename: Rachelle J
authors.initials: RJ
authors.lastname: Bienstock
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Longley
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Mancuso
authors.forename: Purificación
authors.initials: P
authors.lastname: Gutiérrez Ríos
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: William C
authors.initials: WC
authors.lastname: Copeland
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
mesh_terms: D000328:Adult; D000748:Anemia, Macrocytic / Q000150:complications / Q000235:genetics; D001259:Ataxia / Q000150:complications / Q000235:genetics; D001706:Biopsy; D015139:Blotting, Southern; D045304:Cytochromes c / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D034281:Dynamins / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics*; D034381:Hearing Loss / Q000209:etiology* / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000150:complications / Q000235:genetics; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008958:Models, Molecular; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics; D009886:Ophthalmoplegia / Q000150:complications* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014786:Vision Disorders / Q000209:etiology* / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D016274:Oncogene Protein p55(v-myc); D019344:Lactic Acid; D045304:Cytochromes c; D013385:Succinate Dehydrogenase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D034281:Dynamins