title: Deletion of 5' sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome.
abstract: 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.
authors.affiliation: Laboratory of Medical Genetics, Faculte de Medecine, Strasbourg, France. vincent.laugel@chru-strasbourg.fr
authors.forename: Vincent
authors.initials: V
authors.lastname: Laugel
authors.forename: Cecile
authors.initials: C
authors.lastname: Dalloz
authors.forename: Anne
authors.initials: A
authors.lastname: Stary
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Michel
authors.initials: M
authors.lastname: Renouil
authors.forename: Alain
authors.initials: A
authors.lastname: Fourmaintraux
authors.forename: Renier
authors.initials: R
authors.lastname: Velez-Cruz
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.forename: Helene
authors.initials: H
authors.lastname: Dollfus
mesh_terms: D001921:Brain / Q000473:pathology; D003057:Cockayne Syndrome / Q000235:genetics* / Q000503:physiopathology; D004265:DNA Helicases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D018895:Microsatellite Repeats / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes