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Free keywords:
Adult
Amino Acid Sequence
Animals
DNA Polymerase gamma
DNA Replication/genetics
DNA, Mitochondrial/genetics
DNA-Directed DNA Polymerase/*genetics/*metabolism
Disease Models, Animal
Drosophila melanogaster/genetics
Female
Humans
Infant
Mitochondria/genetics
Mutation/genetics
Ophthalmoplegia, Chronic Progressive External/enzymology
Pedigree
Phenotype
Abstract:
Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction.
