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.