NDLI: mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae

Content Provider	PubMed Central
Author	Stumpf, Jeffrey D. Bailey, Christopher M. Spell, Diana Stillwagon, Matthew Anderson, Karen S. Copeland, William C.
Copyright Year	2010
Abstract	DNA polymerase γ (pol γ) is responsible for replication and repair of mitochondrial DNA (mtDNA). Over 150 mutations in POLG (which encodes pol γ) have been discovered in patients with mitochondrial disorders including Alpers, progressive external ophthalmoplegia and ataxia-neuropathy syndrome. However, the severity and dominance of many POLG disease-associated mutations are unclear, because they have been reported in sporadic cases. To understand the consequences of pol γ disease-associated mutations in vivo, we identified dominant and recessive changes in mtDNA mutagenesis, depletion and mitochondrial dysfunction caused by 31 mutations in the conserved regions of the gene, MIP1, which encodes the Saccharomyces cerevisiae ortholog of human pol γ. Twenty mip1 mutant enzymes were shown to disrupt mtDNA replication and may be sufficient to cause disease. Previously uncharacterized sporadic mutations, Q308H, R807C, G1076V, R1096H and S1104C, caused decreased polymerase activity leading to mtDNA depletion and mitochondrial dysfunction. We present evidence showing a limited role of point mutagenesis by these POLG mutations in mitochondrial dysfunction and disease progression. Instead, most mitochondrial defective mip1 mutants displayed reduced or depleted mtDNA. We also determined that the severity of the phenotype of the mip1 mutant strain correlates with the age of onset of disease associated with the human ortholog. Finally, we demonstrated that increasing nucleotide pools by overexpression of ribonucleotide reductase (RNR1) suppressed mtDNA replication defects caused by several dominant mip1 mutations, and the orthologous human mutations revealed severe nucleotide binding defects.
Related Links	http://dx.doi.org/10.1093/hmg/ddq089
Ending Page	2133
Page Count	11
Starting Page	2123
File Format	PDF
ISSN	09646906
e-ISSN	14602083
Journal	Human Molecular Genetics
Issue Number	11
Volume Number	19
Language	English
Publisher	Oxford University Press
Publisher Date	2010-06-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Genetics(clinical) Genetics Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Genetics (clinical)

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