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Lookup NU author(s): Professor Rita HorvathORCiD, Professor Gavin Hudson, Professor Hanns Lochmuller, Professor Bobby McFarlandORCiD, Dr Vankateswara Ramesh, Dr Roger Santer, Professor Robert Taylor, Emeritus Professor Doug Turnbull, Professor Patrick Chinnery
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. © The Author 2006. Published by Oxford University Press. All rights reserved.
Author(s): Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S, Lamantea E, Prokisch H, Lochmuller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Hanna M, Fialho D, Suomalainen A, Zeviani M, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2006
Volume: 129
Issue: 7
Pages: 1674-1684
Date deposited: 23/02/2010
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/brain/awl088
DOI: 10.1093/brain/awl088
PubMed id: 16621917
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