Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome.

PloS One
Kirsten E HoffWilliam C Copeland

Abstract

Mutations in mitochondrial DNA (mtDNA) have been linked to a variety of metabolic, neurological and muscular diseases which can present at any time throughout life. MtDNA is replicated by DNA polymerase gamma (Pol γ), twinkle helicase and mitochondrial single-stranded binding protein (mtSSB). The Pol γ holoenzyme is a heterotrimer consisting of the p140 catalytic subunit and a p55 homodimeric accessory subunit encoded by the nuclear genes POLG and POLG2, respectively. The accessory subunits enhance DNA binding and promote processive DNA synthesis of the holoenzyme. Mutations in either POLG or POLG2 are linked to disease and adversely affect maintenance of the mitochondrial genome, resulting in depletion, deletions and/or point mutations in mtDNA. A homozygous mutation located at Chr17: 62492543G>A in POLG2, resulting in R182W substitution in p55, was previously identified to cause mtDNA depletion and fatal hepatic liver failure. Here we characterize this homozygous R182W p55 mutation using in vivo cultured cell models and in vitro biochemical assessments. Compared to control fibroblasts, homozygous R182W p55 primary dermal fibroblasts exhibit a two-fold slower doubling time, reduced mtDNA copy number and reduced levels of POLG ...Continue Reading

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Citations

Nov 17, 2019·Journal of Clinical Medicine·Loredana Moro
Apr 13, 2020·Clinics and Research in Hepatology and Gastroenterology·Irena JankowskaPiotr Socha
Nov 5, 2020·Carcinogenesis·Jaimin PatelVilhelm A Bohr
Jul 3, 2021·International Journal of Molecular Sciences·Javier RamónRamon Martí

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Methods Mentioned

BETA
exome sequencing
biopsies
PCR
electrophoretic mobility shift assay
size exclusion chromatography
size
light scattering
Differential Scanning Fluorimetry
sizing

Software Mentioned

MathWorks
PolyPhen
ThermoQ application
DMAN
MATLAB
ImageJ64

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