Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome

PLoS Biol. 2007 Jan;5(1):e2. doi: 10.1371/journal.pbio.0050002.


Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

Publication types

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

MeSH terms

  • Aging
  • Animals
  • Antioxidants / pharmacology
  • Cockayne Syndrome / etiology
  • Cockayne Syndrome / genetics*
  • DNA Repair Enzymes / genetics
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • Diethylhexyl Phthalate / pharmacology
  • Fatty Acids / biosynthesis
  • Genome / genetics*
  • Glucose / metabolism
  • Growth Hormone / genetics*
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly-ADP-Ribose Binding Proteins
  • Radiation, Ionizing
  • Somatotrophs / metabolism
  • Xeroderma Pigmentosum Group A Protein / genetics


  • Antioxidants
  • DNA-Binding Proteins
  • Fatty Acids
  • Poly-ADP-Ribose Binding Proteins
  • Xeroderma Pigmentosum Group A Protein
  • Xpc protein, mouse
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Diethylhexyl Phthalate
  • Ercc6 protein, mouse
  • DNA Repair Enzymes
  • Glucose