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Genomic integrity and mitochondrial metabolism defects in Warsaw syndrome cells: a comparison with Fanconi anemia.
- Source :
-
Journal of cellular physiology [J Cell Physiol] 2021 Aug; Vol. 236 (8), pp. 5664-5675. Date of Electronic Publication: 2021 Jan 11. - Publication Year :
- 2021
-
Abstract
- Warsaw breakage syndrome (WABS), is caused by biallelic mutations of DDX11, a gene coding a DNA helicase. We have recently reported two affected sisters, compound heterozygous for a missense (p.Leu836Pro) and a frameshift (p.Lys303Glufs*22) variant. By investigating the pathogenic mechanism, we demonstrate the inability of the DDX11 p.Leu836Pro mutant to unwind forked DNA substrates, while retaining DNA binding activity. We observed the accumulation of patient-derived cells at the G2/M phase and increased chromosomal fragmentation after mitomycin C treatment. The phenotype partially overlaps with features of the Fanconi anemia cells, which shows not only genomic instability but also defective mitochondria. This prompted us to examine mitochondrial functionality in WABS cells and revealed an altered aerobic metabolism. This opens the door to the further elucidation of the molecular and cellular basis of an impaired mitochondrial phenotype and sheds light on this fundamental process in cell physiology and the pathogenesis of these diseases.<br /> (© 2021 Wiley Periodicals LLC.)
- Subjects :
- Abnormalities, Multiple genetics
DEAD-box RNA Helicases genetics
DNA Helicases metabolism
Fanconi Anemia metabolism
Genomics
Humans
Kearns-Sayre Syndrome genetics
Mitochondrial Myopathies genetics
Mutation genetics
DNA Helicases genetics
Fanconi Anemia genetics
Genomic Instability genetics
Kearns-Sayre Syndrome metabolism
Mitochondrial Myopathies metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4652
- Volume :
- 236
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of cellular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 33432587
- Full Text :
- https://doi.org/10.1002/jcp.30265