UV-sensitive syndrome (UVSS) is an autosomal recessive disorder characterised by sun-sensitivity and mild cutaneous symptoms resulting from defects in transcription-coupled repair (TC-NER), the sub-pathway of nucleotide excision repair that rapidly removes UV-induced damage from the transcribed strand of active genes. Cockayne syndrome (CS) is another genetic disorder defective in TC-NER showing developmental and neurological abnormalities and premature ageing. CS is caused by mutations in the CSA or CSB gene whereas UVSS is due to mutations in CSB (2 cases) or in a still unidentified gene (4 cases).
We have characterised at the cellular, genetic and molecular level a French patient, designated UVSS1VI, who shows the mild clinical features suggestive for UVSS. We found that UVSS1VI was mutated in the CSA gene, thus representing a third complementation group of UVSS. This mutation, which had not been described previously, is predicted to cause a trp361cys substitution. Unexpectedly, the sensitivity to oxidative stress of UVSS1 cells appeared to be in the normal range whereas fibroblasts from CS patients mutated in the CSA or CSB gene are hypersensitive to oxidants. Accordingly, the ectopic expression of the CSA gene cloned from UVSS1VI does not restore the altered response to UV of the CS-A cells CS3BE, but it does increase their resistance to oxidative stress. These findings imply that the substitution trp361cys, resulting from the CSA mutation detected in UVSS1VI, affects the function of CSA in UV-induced TC-NER but does not interfere substantially with the role of CSA in the removal of cytotoxic oxidative DNA lesions.
Thus, investigations on UVSS patients, despite the rarity of this disorder, indicate that defects in TC-NER alone cause mild cutaneous alterations and provide further evidence that the additional features present in CS patients, namely precocious aging and deficiencies in mental and physical development, reflect additional roles of the CSA and CSB proteins in the removal of oxidative damage.
Reference: Nardo T (1), Oneda R (1), Spivak G (2), Vaz B (1), Mortier L (3), Thomas P (3), Orioli D (1), Laugel V (4), Stary A (4), Hanawalt PC (2), Sarasin A (4) and Stefanini M (1) . A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc Natl Acad Sci USA, 106: 6209-6214, 2009.
1) Istituto di Genetica Molecolare CNR, Pavia, Italy; 2) Department of Biological Sciences, Stanford University, USA; 3) Clinique de dermatologie, Lille, France; 4) Institut Gustave Roussy, Villejuif, France
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