PUBLICATION
ercc6 deficient zebrafish exhibit UV and metronidazole sensitivity, increased oxygen consumption, and impaired hair cell mechanoelectrical transduction which can be restored by the superoxide dismutase mimetic MnTBAP
- Authors
- Hernandez Herrera, G.A., Dugdale, J.A., Wallace, J.G., Cotter, R.P., Jolliffe, A.M., Clark, K.J., Schimmenti, L.A.
- ID
- ZDB-PUB-260113-16
- Date
- 2026
- Source
- Human molecular genetics : (Journal)
- Registered Authors
- Clark, Karl, Schimmenti, Lisa A.
- Keywords
- Cockayne Syndrome, hair cells, mechanoelectrical transduction, oxygen consumption rates, zebrafish
- MeSH Terms
-
- Animals
- Cockayne Syndrome*/drug therapy
- Cockayne Syndrome*/genetics
- Cockayne Syndrome*/metabolism
- Cockayne Syndrome*/pathology
- DNA Helicases*/deficiency
- DNA Helicases*/genetics
- DNA Repair
- DNA Repair Enzymes*/genetics
- Disease Models, Animal
- Hair Cells, Auditory*/drug effects
- Hair Cells, Auditory*/metabolism
- Hair Cells, Auditory*/pathology
- Humans
- Mechanotransduction, Cellular/drug effects
- Metronidazole*/adverse effects
- Metronidazole*/pharmacology
- Mitochondria/drug effects
- Mitochondria/metabolism
- Oxygen Consumption/drug effects
- Poly-ADP-Ribose Binding Proteins*/genetics
- Superoxide Dismutase/metabolism
- Ultraviolet Rays/adverse effects
- Zebrafish/genetics
- Zebrafish Proteins*/genetics
- PubMed
- 41527836 Full text @ Hum. Mol. Genet.
Citation
Hernandez Herrera, G.A., Dugdale, J.A., Wallace, J.G., Cotter, R.P., Jolliffe, A.M., Clark, K.J., Schimmenti, L.A. (2026) ercc6 deficient zebrafish exhibit UV and metronidazole sensitivity, increased oxygen consumption, and impaired hair cell mechanoelectrical transduction which can be restored by the superoxide dismutase mimetic MnTBAP. Human molecular genetics. :.
Abstract
Cockayne Syndrome is an ultra-rare premature aging condition associated with UV sensitivity, neurocognitive decline, retinopathy, metronidazole-induced lethality, and sensorineural hearing loss. In 70% of affected patients, bi-allelic pathogenic variants in ERCC6 are identified. Although the role of ERCC6 in DNA damage repair has been studied, little is known about the mechanism for defective ERCC6 function in clinical findings, particularly hearing loss. To identify the mechanism of disease caused by pathogenic variants in ERCC6, we developed a zebrafish (Danio rerio) ercc6 loss of function model. We assessed survival after UV and metronidazole exposure, measured basal respiration rates, and evaluated mechanoelectrical transduction function and counts of lateral line hair cells. We found that UV exposure significantly reduces ercc6-/- larval viability. Metronidazole treatment results in complete lethality; wildtype controls show nearly complete survival. ercc6-/- embryos have significantly increased oxygen consumption, suggesting abnormal mitochondrial function. Phalloidin staining of lateral line hair cells with and without UV treatment shows no difference in hair cell counts per neuromast between treatment groups. Mechanoelectrical transduction function after UV exposure, measured by FM1-43 uptake, is reduced. Metronidazole lethality is reduced, oxygen consumption rates are restored, and mechanoelectrical transduction function is preserved by treatment with Mn(III)tetrakis(4-benzoic acid)porphyrin Chloride (MnTBAP), a superoxide dismutase mimetic. We propose that defective mitochondrial function and increased reactive oxygen species levels provide a mechanism for hair cell dysfunction in this model of Cockayne Syndrome. These results provide a foundation for further experiments to explore disease mechanisms and treatment modalities for this premature aging condition.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping