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A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma

Journal article
Authors Triinu Siibak
P. Clemente
A. Bratic
H. Bruhn
T. E. S. Kauppila
Bertil Macao
F. A. Schober
N. Lesko
R. Wibom
K. Naess
I. Nennesmo
A. Wedell
Bradley Peter
C. Freyer
Maria Falkenberg
Published in Human Molecular Genetics
Volume 26
Issue 13
Pages 2515-2525
ISSN 0964-6906
Publication year 2017
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2515-2525
Language en
Links https://doi.org/10.1093/hmg/ddx146
Keywords progressive external ophthalmoplegia, kearns-sayre syndrome, saccharomyces-cerevisiae, mtdna deletions, mutations, replication, fidelity, defects, cells, polg, Biochemistry & Molecular Biology, Genetics & Heredity
Subject categories Genetics, Biochemistry and Molecular Biology

Abstract

Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction.

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