title: Predicting the contribution of novel POLG mutations to human disease through analysis in yeast model.
abstract: The yeast Saccharomyces cerevisiae was used to validate the pathogenic significance of eight human mutations in the gene encoding for the mitochondrial DNA polymerase gamma, namely G303R, S305R, R386H, R574W, P625R, D930N, K947R and P1073L, among which three are novel and four are of unclear pathological significance. Mitochondrial DNA extended and point mutability as well as dominance/recessivity of each mutation has been evaluated. The analysis in yeast revealed that two mutations, S305R and R386H, cannot be the sole cause of pathology observed in patients. These data led us to search for a second mutation in compound with S305R and we found a mutation, P1073L, missed in the first genetic analysis. Finally, a significant rescue of extended mutability has been observed for several dominant mutations by treatment with mitochondrial antioxidants.
authors.affiliation: Department of Genetics, University of Parma, Parma, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Baruffini
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.forename: Birgit
authors.initials: B
authors.lastname: Czermin
authors.forename: Eleonora
authors.initials: E
authors.lastname: Lamantea
authors.forename: Laurence
authors.initials: L
authors.lastname: Bindoff
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.forename: Iliana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Lodi
mesh_terms: D000595:Amino Acid Sequence; D000975:Antioxidants / Q000494:pharmacology; D004256:DNA Polymerase I / Q000235:genetics*; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D000975:Antioxidants; D029701:Saccharomyces cerevisiae Proteins; D004256:DNA Polymerase I; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C068352:MIP1 protein, S cerevisiae; C413027:POLG protein, human