Cockayne syndrome group B (Csb) and group a (Csa) deficiencies predispose to hearing loss and cochlear hair cell degeneration in mice

J Neurosci. 2015 Mar 11;35(10):4280-6. doi: 10.1523/JNEUROSCI.5063-14.2015.


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 (CSB(m/m) mice) and Csa gene (Csa(-/-) mice), respectively. Csb(m/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 Csb(m/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.

Keywords: Cockayne syndrome; DNA damage; DNA repair; csb/csa; hair cell; hearing loss.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Age Factors
  • Animals
  • Cell Death / genetics
  • Cochlea / pathology*
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Disease Progression
  • Evoked Potentials, Auditory, Brain Stem / genetics
  • Genetic Predisposition to Disease / genetics*
  • Hair Cells, Auditory, Inner / pathology*
  • Hearing Loss / complications
  • Hearing Loss / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Degeneration / genetics*
  • Otoacoustic Emissions, Spontaneous / genetics
  • Poly-ADP-Ribose Binding Proteins
  • Proteins / genetics*
  • Proteins / metabolism


  • Ckn1 protein, mouse
  • DNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Proteins
  • Ercc6 protein, mouse
  • DNA Repair Enzymes