Siibak, Triinu, Clemente, Paula, Bratic, Ana, Bruhn, Helene, Kauppila, Timo E. S., Macao, Bertil, Schober, Florian A., Lesko, Nicole, Wibom, Rolf, Naess, Karin ORCID: 0000-0003-4310-7927, Nennesmo, Inger, Wedell, Anna, Peter, Bradley, Freyer, Christoph ORCID: 0000-0003-0418-1673, Falkenberg, Maria and Wredenberg, Anna ORCID: 0000-0002-2500-6121 (2017). A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma. Hum. Mol. Genet., 26 (13). S. 2515 - 2526. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Siibak, TriinuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clemente, PaulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bratic, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruhn, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kauppila, Timo E. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Macao, BertilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schober, Florian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesko, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wibom, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naess, KarinUNSPECIFIEDorcid.org/0000-0003-4310-7927UNSPECIFIED
Nennesmo, IngerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wedell, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peter, BradleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freyer, ChristophUNSPECIFIEDorcid.org/0000-0003-0418-1673UNSPECIFIED
Falkenberg, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wredenberg, AnnaUNSPECIFIEDorcid.org/0000-0002-2500-6121UNSPECIFIED
URN: urn:nbn:de:hbz:38-226944
DOI: 10.1093/hmg/ddx146
Journal or Publication Title: Hum. Mol. Genet.
Volume: 26
Number: 13
Page Range: S. 2515 - 2526
Date: 2017
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; KEARNS-SAYRE SYNDROME; SACCHAROMYCES-CEREVISIAE; MTDNA DELETIONS; MUTATIONS; REPLICATION; FIDELITY; DEFECTS; CELLS; POLGMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22694

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