Phenotypic spectrum associated with mutations of the mitochondrial polymerase geneстатья из журнала
Аннотация: Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (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.
Год издания: 2006
Авторы: Rita Horváth, Gavin Hudson, Giovanfrancesco Ferrari, Nancy Fütterer, Sofia Ahola, Eleonora Lamantea, Holger Prokisch, Hanns Lochmüller, Robert McFarland, Ramesh, Thomas Klopstock, Peter Freisinger, Fabrizio Salvi, Johannes A. Mayr, R Santer, Markéta Tesařová, J Zeman, Bjarne Udd, Rachael W. Taylor, Douglass M. Turnbull, Michael G. Hanna, Doreen Fialho, Anu Suomalainen, Massimo Zeviani, Patrick F. Chinnery
Издательство: Oxford University Press
Источник: Brain
Ключевые слова: Mitochondrial Function and Pathology, Metabolism and Genetic Disorders, ATP Synthase and ATPases Research
Открытый доступ: closed
Том: 129
Выпуск: 7
Страницы: 1674–1684