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Cockayne syndrome is caused by biallelic ERCC8 (CSA) or ERCC6 (CSB) mutations and is characterized by growth restriction, microcephaly, developmental delay, and premature pathological aging. Typically affected patients also have dermal photosensitivity. Although Cockayne syndrome is considered a DNA repair disorder, patients with UV-sensitive syndrome, with ERCC8 (CSA) or ERCC6 (CSB) mutations have indistinguishable DNA repair defects, but none of the extradermal features of Cockayne syndrome. We report novel missense mutations affecting a conserved loop in the ERCC6 (CSB) protein, associated with the Cockayne syndrome phenotype. Indeed, the amino acid sequence of this loop is more highly conserved than the adjacent helicase motifs V and VI, suggesting that this is a crucial structural component of the SWI/SNF family of proteins, to which ERCC6 (CSB) belongs. These comprise two RecA-like domains, separated by an interdomain linker, which interact through helicase motif VI. As the observed mutations are likely to act through destabilizing the tertiary protein structure, this prompted us to re-evaluate ERCC6 (CSB) mutation data in relation to the structure of SWI/SNF proteins. Our analysis suggests that antimorphic mutations cause Cockayne syndrome and that biallelic interdomain linker deletions produce more severe phenotypes. Based on our observations, we propose that further investigation of the pathogenic mechanisms underlying Cockayne syndrome should focus on the effect of antimorphic rather than null ERCC6 (CSB) mutations. (c) 2016 Wiley Periodicals, Inc.
Author(s): Wilson BT, Lochan A, Stark Z, Sutton RE
Publication type: Article
Publication status: Published
Journal: American Journal of Medical Genetics Part A
Year: 2016
Volume: 170
Issue: 3
Pages: 773-776
Print publication date: 01/03/2016
Online publication date: 08/01/2016
Acceptance date: 30/11/2015
ISSN (print): 1552-4825
ISSN (electronic): 1552-4833
Publisher: Wiley-Blackwell
URL: http://dx.doi.org/10.1002/ajmg.a.37501
DOI: 10.1002/ajmg.a.37501
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