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Open Access Green as soon as Postprint is submitted to ZB.
Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.
Brain 129, 1674-1684 (2006)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
mitochondrial encephalopathy; mitochondrial DNA; chronic progressive external ophthalmoplegia; Alpers syndrome
ISSN (print) / ISBN
0006-8950
e-ISSN
1460-2156
Journal
Brain: A Journal of Neurology
Quellenangaben
Volume: 129,
Issue: 7,
Pages: 1674-1684
Publisher
Oxford University Press
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Human Genetics (IHG)