Novel missense mutations in a conserved loop between ERCC6 (CSB) helicase motifs V and VI: Insights into Cockayne syndrome

Am J Med Genet A. 2016 Mar;170(3):773-6. doi: 10.1002/ajmg.a.37501. Epub 2016 Jan 8.


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.

Keywords: Cockayne syndrome; Cockayne syndrome protein B (CSB); ERCC6.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Child, Preschool
  • Cockayne Syndrome / diagnosis
  • Cockayne Syndrome / genetics*
  • DNA Helicases / chemistry
  • DNA Helicases / genetics*
  • DNA Repair Enzymes / chemistry
  • DNA Repair Enzymes / genetics*
  • Facies
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Kyphosis / diagnostic imaging
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Phenotype
  • Poly-ADP-Ribose Binding Proteins
  • Protein Conformation
  • Protein Interaction Domains and Motifs / genetics*
  • Sequence Alignment
  • Sequence Analysis, DNA


  • Poly-ADP-Ribose Binding Proteins
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes