RT Journal Article
SR Electronic
T1 Cockayne Syndrome Group B (Csb) and Group A (Csa) Deficiencies Predispose to Hearing Loss and Cochlear Hair Cell Degeneration in Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4280
OP 4286
DO 10.1523/JNEUROSCI.5063-14.2015
VO 35
IS 10
A1 A. Paul Nagtegaal
A1 Robert N. Rainey
A1 Ingrid van der Pluijm
A1 Renata M.C. Brandt
A1 Gijsbertus T.J. van der Horst
A1 J. Gerard G. Borst
A1 Neil Segil
YR 2015
UL http://www.jneurosci.org/content/35/10/4280.abstract
AB Sensory hair cells in the cochlea, like most neuronal populations that are postmitotic, terminally differentiated, and non-regenerating, depend on robust mechanisms of self-renewal for lifelong survival. We report that hair cell homeostasis requires a specific sub-branch of the DNA damage nucleotide excision repair pathway, termed transcription-coupled repair (TCR). Cockayne syndrome (CS), caused by defects in TCR, is a rare DNA repair disorder with a broad clinical spectrum that includes sensorineural hearing loss. We tested hearing and analyzed the cellular integrity of the organ of Corti in two mouse models of this disease with mutations in the Csb gene (CSBm/m mice) and Csa gene (Csa−/− mice), respectively. Csbm/m and Csa−/− mice manifested progressive hearing loss, as measured by an increase in auditory brainstem response thresholds. In contrast to wild-type mice, mutant mice showed reduced or absent otoacoustic emissions, suggesting cochlear outer hair cell impairment. Hearing loss in Csbm/m and Csa−/− mice correlated with progressive hair cell loss in the base of the organ of Corti, starting between 6 and 13 weeks of age, which increased by 16 weeks of age in a basal-to-apical gradient, with outer hair cells more severely affected than inner hair cells. Our data indicate that the hearing loss observed in CS patients is reproduced in mouse models of this disease. We hypothesize that accumulating DNA damage, secondary to the loss of TCR, contributes to susceptibility to hearing loss.