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

Authors: Van der Pluijm, I  Garinis, GA  Brandt, RM  Gorgels, TG  Wijnhoven, SW  Diderich, KE  De Wit, J  Mitchell, JR  Van Oostrom, C  Beems, R  Niedernhofer, LJ  Velasco, S  Friedberg, EC  Tanaka, K  Van Steeg, H  Hoeijmakers, JH  Van der Horst, GT 
Citation: van der Pluijm I, etal., PLoS Biol. 2007 Jan;5(1):e2.
Pubmed: (View Article at PubMed) PMID:17326724
DOI: Full-text: 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.

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CRRD Object Information
CRRD ID: 10003139
Created: 2015-05-04
Species: All species
Last Modified: 2015-05-04
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.