Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene

Rita Horvath, Gavin Hudson, Gianfrancesco Ferrari, Nancy Fütterer, Sofia Ahola, Eleonora Lamantea, Holger Prokisch, Hanns Lochmüller, Robert McFarland, V. Ramesh, Thomas Klopstock, Peter Freisinger, Fabrizio Salvi, Johannes A. Mayr, Rene Santer, Marketa Tesarova, Jiri Zeman, Bjarne Udd, Robert W. Taylor, Douglass TurnbullMichael Hanna, Doreen Fialho, Anu Suomalainen, Massimo Zeviani, Patrick F. Chinnery

Research output: Contribution to journalArticle

Abstract

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase γ (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G→A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G→A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.

Original languageEnglish
Pages (from-to)1674-1684
Number of pages11
JournalBrain
Volume129
Issue number7
DOIs
Publication statusPublished - Jul 2006

Keywords

  • Alpers syndrome
  • Chronic progressive external ophthalmoplegia
  • Mitochondrial DNA
  • Mitochondrial encephalopathy
  • mtDNA
  • Polymerase gamma

ASJC Scopus subject areas

  • Neuroscience(all)

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    Horvath, R., Hudson, G., Ferrari, G., Fütterer, N., Ahola, S., Lamantea, E., Prokisch, H., Lochmüller, H., McFarland, R., Ramesh, V., Klopstock, T., Freisinger, P., Salvi, F., Mayr, J. A., Santer, R., Tesarova, M., Zeman, J., Udd, B., Taylor, R. W., ... Chinnery, P. F. (2006). Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene. Brain, 129(7), 1674-1684. https://doi.org/10.1093/brain/awl088