MUTATION REPORTS

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

J D Stewart¹, S Tennant², H Powell², A Pyle¹, E L Blakely¹, L He¹, G Hudson¹, M Roberts³, D du Plessis³, D Gow³, L D Mewasingh⁴, M G Hanna⁵, S Omer⁶, A A Morris⁷, R Roxburgh⁸, J H Livingston⁹, R McFarland¹, D M Turnbull^1,2, P F Chinnery^1,2, R W Taylor^1,2

¹ Mitochondrial Research Group, The Medical School, Newcastle University, Newcastle upon Tyne, UK
² Institutes of Ageing and Health and Human Genetics, Newcastle University, UK
³ Departments of Neurology and Neuropathology, Hope Hospital, Salford, UK
⁴ Department of Paediatric Neurology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
⁵ Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK
⁶ Department of Neurology, St George’s Hospital, London, UK
⁷ Willink Unit, Royal Manchester Children’s Hospital, Manchester, UK
⁸ Auckland City Hospital, Private Bag 92-024, Auckland, New Zealand
⁹ Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

Correspondence to:
Professor R W Taylor, Mitochondrial Research Group, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; r.w.taylor{at}ncl.ac.uk

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Blok, M J, van den Bosch, B J, Jongen, E, Hendrickx, A, de Die-Smulders, C E, Hoogendijk, J E, Brusse, E, de Visser, M, Poll-The, B T, Bierau, J, de Coo, I F, Smeets, H J (2009). The unfolding clinical spectrum of POLG mutations. J. Med. Genet. 46: 776-785 [Abstract] [Full Text]  
• Kasiviswanathan, R., Longley, M. J., Chan, S. S. L., Copeland, W. C. (2009). Disease Mutations in the Human Mitochondrial DNA Polymerase Thumb Subdomain Impart Severe Defects in Mitochondrial DNA Replication. J. Biol. Chem. 284: 19501-19510 [Abstract] [Full Text]