A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma

• Published in: Human molecular genetics Vol. 26; no. 13; pp. 2515 - 2525
• Main Authors: Siibak, Triinu, Clemente, Paula, Bratic, Ana, Bruhn, Helene, Kauppila, Timo E S, Macao, Bertil, Schober, Florian A, Lesko, Nicole, Wibom, Rolf, Naess, Karin, Nennesmo, Inger, Wedell, Anna, Peter, Bradley, Freyer, Christoph, Falkenberg, Maria, Wredenberg, Anna
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-07-2017
• Subjects: Adult; Amino Acid Sequence; Animals; Biochemistry & Molecular Biology; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; cells; defects; Disease Models, Animal; DNA Polymerase gamma; DNA Replication - genetics; DNA, Mitochondrial - genetics; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Drosophila melanogaster - genetics; Female; fidelity; Genetics; Genetics & Heredity; Genetik; Humans; Infant; kearns-sayre syndrome; Medicin och hälsovetenskap; Mitochondria - genetics; mtdna deletions; Mutation - genetics; mutations; Ophthalmoplegia, Chronic Progressive External - enzymology; Pedigree; Phenotype; polg; progressive external ophthalmoplegia; replication; saccharomyces-cerevisiae
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddx146

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.