Stewart, J. D., Tennant, S., Powell, H., Pyle, A., Blakely, E. L., He, L., Hudson, G., Roberts, M., du Plessis, D., Gow, D., Mewasingh, L .D., Hanna, M. G., Omer, S., Morris, A. A., Roxburgh, R., Livingston, J. H., McFarland, R., Turnbull, D. M., Chinnery, P .F. and Taylor, R .W. (2009) Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. Journal of Medical Genetics, 46, 209-214. (doi:10.1136/jmg.2008.058180). (PMID:19251978)
Abstract
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.
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