Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children
| Autor: | Angela Pyle, Michael G. Hanna, S.E. Omer, Joanna Stewart, Gavin Hudson, D du Plessis, H Powell, Emma L. Blakely, David W. Gow, Douglass M. Turnbull, Mark E Roberts, L D Mewasingh, Robert W. Taylor, S. Tennant, Robert McFarland, Richard Roxburgh, John H. Livingston, A. A. M. Morris, Patrick F. Chinnery, Langping He |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Mitochondrial DNA Ophthalmoplegia Chronic Progressive External Mitochondrial Diseases Adolescent Mitochondrial disease Mutation Missense Cytochrome-c Oxidase Deficiency DNA-Directed DNA Polymerase Biology medicine.disease_cause Genetics medicine Cytochrome c oxidase Missense mutation Humans Child Muscle Skeletal Gene Genetics (clinical) Polymerase Mutation Infant Diffuse Cerebral Sclerosis of Schilder Middle Aged medicine.disease DNA Polymerase gamma Liver biology.protein Female Sequence Alignment Mitochondrial DNA replication |
| Zdroj: | Journal of medical genetics. 46(3) |
| ISSN: | 1468-6244 |
| Popis: | Background: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease. Methods and results: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers– Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids. Conclusion: The addition of these substitutions— including the first report of a dinucleotide mutation (c.1814_1815TT.GC)—to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations. |
| Databáze: | OpenAIRE |
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