Mutation update for theCSB/ERCC6andCSA/ERCC8genes involved in Cockayne syndrome

Abstract

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/ CSA/ and www.umd.be/CSB/). Hum Mutat 31:113-126,

KIAA1530 Protein Is Recruited by Cockayne Syndrome Complementation Group Protein A (CSA) to Participate in Transcription-coupled Repair (TCR)

“…2B). However, when we used the CSA patient cell line (CS3BE) that harbors two point mutations on the CSA gene, which severely impairs the WD40 motif of CSA protein (18,20,24), we found that the UV-induced chromatin accumulation of KIAA1530 was abolished (Fig. 2C).…”

“…Eighteen distinct CSA mutations have been reported to date (24). Most of these point mutations and premature terminations lead to severe CS clinical manifestations, as described above (25).…”

“…This patient does not have any neurological or developmental abnormalities, and the cellular sensitivity to oxidative stress is normal, indicating that this mutant may uncouple the roles of CSA in UV response versus its function in oxidative damage repair (26). So far, the molecular pathology of CS remains poorly understood because of relative heterogeneous cellular and clinical phenotypes of patients carrying mutations on the same gene (14,24). In this study, we identify and characterize KIAA1530, a protein that is recruited to sites of DNA damage by CSA.…”

Mammalian Transcription-Coupled Excision Repair

“…The biochemical and molecular properties are detailed below. Mutational analysis among CS patients showed that for both genes ( 60% CSB and 40% CSA) mutations are scattered over the genes with, to date, no clear genotypephenotype correlation (Laugel et al 2010). …”

Ct shift: A novel and accurate real-time PCR quantification model for direct comparison of different nucleic acid sequences and its application for transposon quantifications

“…PGBD3, one of the PiggyBac derived transposons in the human genome is abundantly expressed in such a fusion form with Cockayne syndrome B (CSB) protein (http://biogps.org/). CSB protein has functions in transcription-coupled nucleotide excision repair (Sarker et al, 2005;Laine and Egly, 2006) and chromatin remodeling (Newman et al, 2006), and mutations of the CSB gene are responsible for 70% of CS disease (Laugel et al, 2010). PGBD3 has been conserved in the 5th intron of CSB gene in Primates, and alternative splicing produces a protein fusion product with the N-terminal part of CSB protein (Newman et al, 2008).…”