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The disease-causing...
The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POL?-related diseases
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- Erdinc, Direnis (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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- Macao, Bertil, 1969 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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- Valenzuela, Sebastian, 1993 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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Lesko, N. (author)
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Naess, K. (author)
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- Peter, Bradley (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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- Bruhn, H. (author)
- Karolinska Institutet
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- Wedell, A. (author)
- Karolinska Institutet
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- Wredenberg, A. (author)
- Karolinska Institutet
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- Falkenberg, Maria, 1968 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: Biochimica Et Biophysica Acta-Molecular Basis of Disease. - 0925-4439 .- 1879-260X. ; 1869:7
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Abstract
Subject headings
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- Mutations in the catalytic domain of mitochondrial DNA polymerase ? (POL?) cause a broad spectrum of clinical conditions. POL? 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 POL?, manifesting a severe clinical phenotype with develop-mental 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 POL? 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 POL? to support leading-strand DNA synthesis with the TWINKLE helicase. Our results thus reveal a novel pathogenic mechanism for POL?-related diseases.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- DNA polymerase & gamma
- TWINKLE helicase
- mtDNA
- Mitochondrial
- replication
- Disease
- DNA-polymerase-gamma
- mitochondrial rna-polymerase
- replication
- maintenance
- stability
- subunit
- binding
- Biochemistry & Molecular Biology
- Biophysics
- Cell Biology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Erdinc, Direnis
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Macao, Bertil, 1 ...
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Valenzuela, Seba ...
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Lesko, N.
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Naess, K.
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Peter, Bradley
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show more...
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Bruhn, H.
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Wedell, A.
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Wredenberg, A.
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Falkenberg, Mari ...
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Biochimica Et Bi ...
- By the university
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University of Gothenburg
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Karolinska Institutet