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Characterizing Histone Post-translational Modification Alterations in Yeast Neurodegenerative Proteinopathy Models
Published on: March 24, 2019
Predicting the contribution of novel POLG mutations to human disease through analysis in yeast model
Enrico Baruffini1, Rita Horvath, Cristina Dallabona
1Department of Genetics, University of Parma, Parma, Italy.
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.
Insights
Yeast studies validated eight human mutations in mitochondrial DNA polymerase gamma. Two mutations, S305R and R386H, are not solely pathogenic, prompting discovery of a compound mutation, P1073L.
Area of Science:
- Genetics
- Molecular Biology
- Mitochondrial Biology
Background:
- Mitochondrial DNA polymerase gamma (POLG) mutations are linked to various neurodegenerative diseases.
- The pathogenic significance of several POLG mutations remains unclear, necessitating functional validation.
- Understanding mutation impact is crucial for diagnosing and potentially treating mitochondrial disorders.
Purpose of the Study:
- To functionally validate eight human mutations in the POLG gene using Saccharomyces cerevisiae.
- To assess the pathogenic significance, mutability, and inheritance patterns of these POLG mutations.
- To investigate the potential therapeutic effect of mitochondrial antioxidants on dominant POLG mutations.
Main Methods:
- Utilized the yeast Saccharomyces cerevisiae as a model system for mutation analysis.
- Evaluated mitochondrial DNA extended and point mutability for each of the eight human POLG mutations.
- Assessed the dominance and recessivity of each mutation in the yeast model.
- Investigated compound mutations and the effect of mitochondrial antioxidants.
Main Results:
- Two mutations, S305R and R386H, were found not to be the sole cause of observed patient pathology.
- A previously missed compound mutation, P1073L, was identified in conjunction with S305R.
- Several dominant mutations showed a significant rescue of extended mutability upon treatment with mitochondrial antioxidants.
Conclusions:
- Functional studies in yeast are essential for clarifying the pathogenic role of POLG mutations.
- Compound mutations can contribute to disease pathology and may be missed in initial analyses.
- Mitochondrial antioxidants show promise in mitigating the effects of certain dominant POLG mutations.
