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: Paola Da Pozzo, Anna Rubegni, Alessandra Rufa, Elena Cardaioli, Ilaria Taglia, Gian Nicola Gallus, Alessandro Malandrini, Antonio Federico
• Journal: Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology (Neurol Sci) Vol. 36 Issue 9 Pg. 1713-5 (Sep 2015) ISSN: 1590-3478 [Electronic] Italy
• PMID: 26050231 (Publication Type: Case Reports, Letter, Research Support, Non-U.S. Gov't)

Chemical References

• Mitochondrial Proteins
• DNA Polymerase gamma
• DNA-Directed DNA Polymerase
• POLG protein, human
• DNA Helicases
• TWNK protein, human

Topics

• Aged, 80 and over
• DNA Helicases (genetics)
• DNA Polymerase gamma
• DNA-Directed DNA Polymerase (genetics)
• Humans
• Male
• Mitochondrial Proteins (genetics)
• Molecular Sequence Data
• Muscle, Skeletal
• Mutation
• Ophthalmoplegia, Chronic Progressive External (genetics, pathology)
• Sequence Homology, Amino Acid