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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⌬ex15]). In the XpgD811stop and Xpg⌬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⌬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.Xeroderma pigmentosum (XP) is a rare autosomal recessive disease clinically characterized by hypersensitivity to sunlight, abnormal pigmentation, and a predisposition to skin cancers, particularly at sun-exposed areas. XP patients are classified into eight complementation groups. Cells of patients from seven out of the eight groups (XP-A to XP-G) exhibit a defect in the early steps of the nucleotide excision repair (NER) pathway, and cells from the remaining group (XP variant) are defective in bypass DNA synthesis across DNA lesions induced by UV radiation (1,23,34).Another sun hypersensitivity disorder, Cockayne syndrome (CS), is both clinically and genetically distinct from XP and is characterized by postnatal growth failure, a short life span, and progressive neurological dysfunction, but no predisposition to cancer (29). To date, more than 140 CS cases have been reported (29) that can be classified into five complementation groups. Most patients exhibit only CS symptoms, and they belong to either group CS-A or CS-B. These symptoms arise from mutations in the CSA or CSB gene, both of which are required for the preferential removal of UV light-induced lesions in transcribed strands of genes by the transcription-coupled repair (TCR) process (14, 36).In very rare cases, complementation analyses have classified some CS patients into XP groups XP-B, XP-D, and XP-G (6,12,13,20,27,37,38). XP-B patients are ...

The translocator protein (TSPO) has been proposed to act as a key component in a complex important for mitochondrial cholesterol importation, which is the rate-limiting step in steroid hormone synthesis. However, TSPO function in steroidogenesis has recently been challenged by the development of TSPO knockout (TSPO-KO) mice, as they exhibit normal baseline gonadal testosterone and adrenal corticosteroid production. Here, we demonstrate that despite normal androgen levels in young male TSPO-KO mice, TSPO deficiency alters steroidogenic flux and results in reduced total steroidogenic output. Specific reductions in the levels of progesterone and corticosterone as well as age-dependent androgen deficiency were observed in both young and aged male TSPO-KO mice. Collectively, these findings indicate that while TSPO is not critical for achieving baseline testicular and adrenal steroidogenesis, either indirect effects of TSPO on steroidogenic processes, or compensatory mechanisms and functional redundancy, lead to subtle steroidogenic abnormalities which become exacerbated with aging.