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J Med Genet. 2009 Mar;46(3):209-14. doi: 10.1136/jmg.2008.058180.

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

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  • 1Mitochondrial Research Group, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.

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.

PMID:
19251978
DOI:
10.1136/jmg.2008.058180
[PubMed - indexed for MEDLINE]
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