The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POLγ-related diseases.

Autor: Erdinc D; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg SE-40530, Sweden., Macao B; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg SE-40530, Sweden., Valenzuela S; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg SE-40530, Sweden., Lesko N; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm SE-17177, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden., Naess K; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm SE-17177, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden., Peter B; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg SE-40530, Sweden., Bruhn H; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm SE-17177, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden., Wedell A; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden., Wredenberg A; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm SE-17177, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. Electronic address: anna.wredenberg@ki.se., Falkenberg M; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg SE-40530, Sweden. Electronic address: maria.falkenberg@medkem.gu.se.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2023 Oct; Vol. 1869 (7), pp. 166786. Date of Electronic Publication: 2023 Jun 10.
DOI: 10.1016/j.bbadis.2023.166786
Abstrakt: Mutations in the catalytic domain of mitochondrial DNA polymerase γ (POLγ) cause a broad spectrum of clinical conditions. POLγ mutations impair mitochondrial DNA replication, thereby causing deletions and/or depletion of mitochondrial DNA, which in turn impair biogenesis of the oxidative phosphorylation system. We here identify a patient with a homozygous p.F907I mutation in POLγ, manifesting a severe clinical phenotype with developmental arrest and rapid loss of skills from 18 months of age. Magnetic resonance imaging of the brain revealed extensive white matter abnormalities, Southern blot of muscle mtDNA demonstrated depletion of mtDNA and the patient deceased at 23 months of age. Interestingly, the p.F907I mutation does not affect POLγ activity on single-stranded DNA or its proofreading activity. Instead, the mutation affects unwinding of parental double-stranded DNA at the replication fork, impairing the ability of the POLγ to support leading-strand DNA synthesis with the TWINKLE helicase. Our results thus reveal a novel pathogenic mechanism for POLγ-related diseases.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
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