Conceptual developments in the causes of Cockayne syndrome

Cockayne syndrome is an autosomal recessive disease that covers a wide range of symptoms, from mild photosensitivity to severe neonatal lethal disorder. The pathology of Cockayne syndrome may be caused by several mechanisms such as a DNA repair deficiency, transcription dysregulation, altered redox balance and mitochondrial dysfunction. Conceivably each of these mechanisms participates during a different stage in life of a Cockayne syndrome patient. Endogenous reactive oxygen is considered as an ultimate cause of DNA damage that contributes to Cockayne syndrome pathology. Here we demonstrate that mitochondrial reactive oxygen does not cause detectable nuclear DNA damage. This observation implies that a significant component of Cockayne syndrome pathology may be due to abnormal mitochondrial function independent of nuclear DNA damage. The source of nuclear DNA damage to central nervous system tissue most likely occurs from extrinsic neurotransmitter signaling.

► Cockayne syndrome is a disease of growth failure, photosensitivity and neurodegeneration.
► Four genes CSA, CSB, UVSSA, USP7 regulate RNA polymerase II and transcription coupled repair.
► CS gene products have an important role in cellular redox balance.
► Reactive oxygen from mitochondria causes cellular autophagy but not nuclear DNA damage.
► CS genes functions in nuclear DNA repair and mitochondrial autophagy may be independent.