Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome

Abstract

UV-sensitive syndrome (UV^sS) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. UV^sS cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage. It was suggested that UV^sS does not belong to any complementation groups of known photosensitive disorders such as xeroderma pigmentosum and Cockayne syndrome (CS). To identify the gene responsible for UV^sS, we performed a microcell-mediated chromosome transfer based on the functional complementation of UV hypersensitivity. We found that one of the UV^sS cell lines, UV^s1KO, acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for CS group B (CSB), which involves neurological abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, we sequenced the CSB gene from UV^s1KO and detected a homozygous null mutation. Our results indicate that previous complementation analysis of UV^s1KO was erroneous. This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities. On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a UV^sS cell line obtained from an unrelated patient, indicating genetic heterogeneity in UV^sS. Possible explanations for the discrepancy in the genotype-phenotype relationship in UV^s1KO are presented.