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Title: Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency

As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which—in a C57BL6/FVB F1 hybrid genetic background—displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types,more » organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.« less
 [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [3] ;  [4] ;  [5] ;  [6] ;  [1] ;  [5] ;  [1] ;  [7] ;  [8]
  1. Erasmus University Medical Center, Rotterdam (The Netherlands). Dept. of Genetics.
  2. Erasmus Univ. Medical Center, Rotterdam (The Netherlands). Dept. of Neuroscience.
  3. VU Univ. Medical Center, Amsterdam (The Netherlands). Dept. of Intensive Care.
  4. Uniklinik Balgrist, Zurich (Switzerland)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division.
  6. Erasmus University Medical Center, Rotterdam (The Netherlands). Dept. of Genetics
  7. Erasmus University Medical Center, Rotterdam (The Netherlands). Dept. of Genetics and Dept. of Vascular Surgery.
  8. The Scripps Research Institute, San Diego, CA (United States)
Publication Date:
OSTI Identifier:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
PLoS Genetics
Additional Journal Information:
Journal Volume: 10; Journal Issue: 10; Journal ID: ISSN 1553-7404
Public Library of Science
Research Org:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE; National Institute of Health
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES DNA damage; mouse models; DNA repair; neocortex; neurons; phenotypes; polymerase chain reaction; nervous system