Ultraviolet-B induced hyperplasia and squamous cell carcinomas in the cornea of XPA-deficient mice.
In Xeroderma Pigmentosum (XP) patients, due to a defective repair of UV-induced DNA damage, neoplastic changes occur in sunlight-exposed areas of the skin and eyes. There are seven complementation groups in XP (XP-A to XP-G). Recently, we have generated XPA-deficient mice (group-A XP) by gene targeting in embryonic stem cells. In order to evaluate UV-B sensitivity, XPA-deficient mice (n = 20), wild type (n = 7) and heterozygous mice (n = 13) were exposed to low daily doses of UV-B for 14 weeks at a cumulative dose of 22 kj m-2 (250-400 nm). For a period of 32 weeks, the mice were checked twice a week for the development of pathology. The UV-B treatment induced eye abnormalities in the XPA-deficient mice. Initially, photophobia was noticed, followed by a loss of transparency of the cornea, eventually affecting nearly all XPA-deficient mice (19 out of 20). In 12 out of 19 mice, the pathology progressed to give eye protrusion. Histology of these eyes showed hyperplasia and squamous cell carcinomas of the corneal epithelium. No eye-lesions were found in control (wild-type and heterozygous) mice that were exposed to the same UV-B dose. The corneal abnormalities found in the XPA-deficient mice appear to be similar to those found in human XP patients. These results confirm the role of the functional XPA gene in protecting the cornea from pathology by UV-B irradiation. In addition, they suggest that the XPA-deficient mouse is a suitable animal model for the study of XPA ocular disorders.
De Vries
A
A
Department of Immunology, University of Utrecht, The Netherlands.
Gorgels
T G
TG
Berg
R J
RJ
Jansen
G H
GH
Van Steeg
H
H
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology*; D003315:Cornea / Q000473:pathology / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005134:Eye Neoplasms / Q000209:etiology*; D006965:Hyperplasia; D051379:Mice; D008817:Mice, Mutant Strains; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014983:Xeroderma Pigmentosum / Q000473:pathology*; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse