Journal
HUMAN MOLECULAR GENETICS
Volume 26, Issue 13, Pages 2515-2525Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx146
Keywords
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Funding
- Swedish Research Council [VR521-2012-2571, VR521-2013-2341, VR521-2013-3621]
- Stockholm County Council [K01762012, 20140053]
- Swedish Foundation for Strategic Research [ICA 12-0017]
- Knut & Alice Wallenberg Foundation [KAW 2013.0026, KAW 2011, KAW 2014]
- Swedish Cancer Foundation [CAN 2016/816]
- European Research Council
- Swedish Brain Foundation [FO2015-0146]
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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.
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