1. ¹Laboratory of Medical Genetics, Faculte de Medecine, Strasbourg, France
2. ²FRE2939, Institut Gustave Roussy, Villejuif, France
3. ³Department of Medical Genetics, Hopital Necker-Enfants Malades, Paris, France
4. ⁴Department of Neuropediatrics, Hopital Necker-Enfants Malades, Paris, France
5. ⁵Department of Pediatrics, Hopital Sud-Reunion, Saint-Pierre-de-la-Réunion, France
6. ⁶Department of Transcription, IGBMC, Illkirch, France

Correspondence: Dr V Laugel, Laboratory of Medical Genetics, Faculte de Medecine, 11 rue Humann, F-67000 Strasbourg, France. Tel: +33 3 90 24 35 62; Fax: + 33 3 90 24 31 10; E-mail: vincent.laugel@chru-strasbourg.fr

Received 2 October 2007; Revised 27 November 2007; Accepted 28 November 2007; Published online 9 January 2008.

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.