TY - JOUR
T1 - Deletion of 5′ sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome
AU - Laugel, Vincent
AU - Dalloz, Cecile
AU - Stary, Anne
AU - Cormier-Daire, Valerie
AU - Desguerre, Isabelle
AU - Renouil, Michel
AU - Fourmaintraux, Alain
AU - Velez-Cruz, Renier
AU - Egly, Jean Marc
AU - Sarasin, Alain
AU - Dollfus, Helene
PY - 2008/3
Y1 - 2008/3
N2 - Cockayne syndrome is an autosomal recessive neurodegenerative disorder characterized by a specific defect in the repair of UV-induced DNA lesions. Most cases of Cockayne syndrome are caused by mutations in the CSB gene but the pathophysiological mechanisms are poorly understood. We report the clinical and molecular data of two severely affected Cockayne patients with undetectable CSB protein and mRNA. Both patients showed severe growth failure, microcephaly, mental retardation, congenital cataracts, retinal pigmentary degeneration, photosensitivity and died at the ages of 6 and 8 years. UV irradiation assays demonstrated that both patients had the classical DNA repair defect. Genomic DNA sequencing of the CSB gene showed a homozygous deletion involving non-coding exon 1 and upstream regulatory sequences, but none of the coding exons. Functional complementation using a wild-type CSB expression plasmid fully corrected the DNA repair defect in transfected fibroblasts. Horibata et al recently proposed that all type of CSB mutations result in a defect in UV damage repair that is responsible for the photosensitivity observed in the syndrome, but that only truncated CSB polypeptides generated by nonsense mutations have some additional inhibitory functions in transcription or in oxidative damage repair, which are necessary to lead to the other features of the phenotype. Our patients do not fit the proposed paradigm and new hypotheses are required to account for the pathophysiology of Cockayne syndrome, at the crossroads between DNA repair and transcription.
AB - Cockayne syndrome is an autosomal recessive neurodegenerative disorder characterized by a specific defect in the repair of UV-induced DNA lesions. Most cases of Cockayne syndrome are caused by mutations in the CSB gene but the pathophysiological mechanisms are poorly understood. We report the clinical and molecular data of two severely affected Cockayne patients with undetectable CSB protein and mRNA. Both patients showed severe growth failure, microcephaly, mental retardation, congenital cataracts, retinal pigmentary degeneration, photosensitivity and died at the ages of 6 and 8 years. UV irradiation assays demonstrated that both patients had the classical DNA repair defect. Genomic DNA sequencing of the CSB gene showed a homozygous deletion involving non-coding exon 1 and upstream regulatory sequences, but none of the coding exons. Functional complementation using a wild-type CSB expression plasmid fully corrected the DNA repair defect in transfected fibroblasts. Horibata et al recently proposed that all type of CSB mutations result in a defect in UV damage repair that is responsible for the photosensitivity observed in the syndrome, but that only truncated CSB polypeptides generated by nonsense mutations have some additional inhibitory functions in transcription or in oxidative damage repair, which are necessary to lead to the other features of the phenotype. Our patients do not fit the proposed paradigm and new hypotheses are required to account for the pathophysiology of Cockayne syndrome, at the crossroads between DNA repair and transcription.
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U2 - 10.1038/sj.ejhg.5201991
DO - 10.1038/sj.ejhg.5201991
M3 - Article
C2 - 18183039
AN - SCOPUS:39749184830
SN - 1018-4813
VL - 16
SP - 320
EP - 327
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -