title: Sporadic PEO caused by a novel POLG variation and a Twinkle mutation: digenic inheritance?
abstract: Progressive external ophthalmoplegia (PEO) with multiple deletions of mitochondrial DNA (mtDNA) is associated with several mutations in nuclear genes. They include POLG, POLG2, ANT1, C10orf2/Twinkle, and OPA1. However, digenic inheritance in mitochondrial disorders has been documented in a few cases over the years. Here we describe an 80-year-old man with sporadic PEO associated with mtDNA deletions. Sequencing of the POLG revealed a novel heterozygous mutation (c.2831A>G; p.Glu944Gly), predicted in silico as damaging, in the patient who also carried a heterozygous mutation in C10orf2/Twinkle (c.1142T>C; p.Leu381Pro). This case provides a second report of a PEO with different mutations in the POLG and C10orf2/Twinkle genes, supporting the hypothesis that the PEO phenotype can be determined by the co-existence of two abnormalities in separate genes, both involved in the maintenance and stability of mtDNA. Finally, this study expands the spectrum of POLG mutations and highlights the need to sequence the whole set of nuclear genes associated with PEO and multiple mtDNA deletions.
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 2, 53100, Siena, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Da Pozzo
authors.forename: Anna
authors.initials: A
authors.lastname: Rubegni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufa
authors.forename: Elena
authors.initials: E
authors.lastname: Cardaioli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Taglia
authors.forename: Gian Nicola
authors.initials: GN
authors.lastname: Gallus
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malandrini
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
mesh_terms: D000369:Aged, 80 and over; D004265:DNA Helicases / Q000235:genetics*; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology; D017386:Sequence Homology, Amino Acid
chemical_list: D024101:Mitochondrial Proteins; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D004265:DNA Helicases; C431576:TWNK protein, human