Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia.

Abstract

DNA polymerase gamma (pol gamma ) is required to maintain the genetic integrity of the 16,569-bp human mitochondrial genome (mtDNA). Mutation of the nuclear gene for the catalytic subunit of pol gamma (POLG) has been linked to a wide range of mitochondrial diseases involving mutation, deletion, and depletion of mtDNA. We describe a heterozygous dominant mutation (c.1352G-->A/p.G451E) in POLG2, the gene encoding the p55 accessory subunit of pol gamma , that causes progressive external ophthalmoplegia with multiple mtDNA deletions and cytochrome c oxidase (COX)-deficient muscle fibers. Biochemical characterization of purified, recombinant G451E-substituted p55 protein in vitro revealed incomplete stimulation of the catalytic subunit due to compromised subunit interaction. Although G451E p55 retains a wild-type ability to bind DNA, it fails to enhance the DNA-binding strength of the p140-p55 complex. In vivo, the disease most likely arises through haplotype insufficiency or heterodimerization of the mutated and wild-type proteins, which promote mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype.

• Authors: Matthew J Longley, Susanna Clark, Cynthia Yu Wai Man, Gavin Hudson, Steve E Durham, Robert W Taylor, Simon Nightingale, Douglass M Turnbull, William C Copeland, Patrick F Chinnery
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 78 Issue 6 Pg. 1026-34 (Jun 2006) ISSN: 0002-9297 [Print] United States
• PMID: 16685652 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Enzyme Inhibitors
• Nucleic Acid Synthesis Inhibitors
• Protein Subunits
• DNA
• Electron Transport Complex IV
• DNA Polymerase gamma
• DNA-Directed DNA Polymerase
• POLG protein, human
• Ethylmaleimide

Topics

• Age of Onset
• Amino Acid Sequence
• Catalytic Domain (genetics)
• DNA (metabolism)
• DNA Polymerase gamma
• DNA, Mitochondrial (analysis, genetics)
• DNA-Directed DNA Polymerase (genetics, metabolism)
• Dimerization
• Electron Transport Complex IV (analysis, metabolism)
• Enzyme Inhibitors (pharmacology)
• Ethylmaleimide (pharmacology)
• Female
• Heterozygote
• Humans
• Middle Aged
• Molecular Sequence Data
• Muscle Fibers, Skeletal (enzymology)
• Muscle, Skeletal (chemistry, enzymology)
• Mutation
• Nucleic Acid Synthesis Inhibitors
• Ophthalmoplegia, Chronic Progressive External (diagnosis, enzymology, genetics)
• Protein Subunits (genetics, metabolism)