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Molecular and Cellular Biology, May 2004, p. 3712-3719, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3712-3719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of the XPG Region That Causes the Onset of Cockayne Syndrome by Using Xpg Mutant Mice Generated by the cDNA-Mediated Knock-In Method

Naoko Shiomi,1 Seiji Kito,1 Masaki Oyama,2 Tsukasa Matsunaga,2 Yoshi-Nobu Harada,3 Masahito Ikawa,4 Masaru Okabe,4 and Tadahiro Shiomi1*

Research Center for Radiation Safety,1 Frontier Research Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555,3 Laboratory of Molecular Human Genetics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-0934,2 Genome Information Research Center, Osaka University, Suita, Osaka 565-0871, Japan4

Received 9 September 2003/ Returned for modification 22 October 2003/ Accepted 26 January 2004

In addition to xeroderma pigmentosum (XP), mutations in the human XPG gene cause early onset of Cockayne syndrome (CS) in some patients (XPG/CS). The CS-causing mutations in such patients all produce truncated XPG proteins. To test the hypothesis that the CS phenotype, with characteristics such as growth retardation and a short life span in XPG/CS patients, results from C-terminal truncations, we constructed mutants with C-terminal truncations in mouse XPG (Xpg) (from residue D811 to the stop codon [XpgD811stop] and deletion of exon 15 [Xpg{Delta}ex15]). In the XpgD811stop and Xpg{Delta}ex15 mutations, the last 360 and 183 amino acids of the protein were deleted, respectively. To generate Xpg mutant mice, we devised the shortcut knock-in method by replacing genomic DNA with a mutated cDNA fragment (cDNA-mediated knock in). The control mice, in which one-half of Xpg genomic DNA fragment was replaced with a normal Xpg cDNA fragment, had a normal growth rate, a normal life span, normal sensitivity to UV light, and normal DNA repair ability, indicating that the Xpg gene partially replaced with the normal cDNA fragment retained normal functions. The XpgD811stop homozygous mice exhibited growth retardation and a short life span, but the Xpg{Delta}ex15 homozygous mice did not, indicating that deletion of the last 360 amino acids results in the CS phenotype but deletion of the last 183 amino acids does not. The XpgD811stop homozygous mice, however, exhibited a slightly milder CS phenotype than did the Xpg null mutant mice, indicating that the XpgD811stop protein still retains some Xpg function that affects the severity of the CS phenotype.

* Corresponding author. Mailing address: Research Center for Radiation Safety, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Phone: 81-43-206-3136. Fax: 81-43-251-9818. E-mail: shiomita{at}nirs.go.jp.

Molecular and Cellular Biology, May 2004, p. 3712-3719, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.3712-3719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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