Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome

Hum Mutat. 2013 Jan;34(1):103-7. doi: 10.1002/humu.22226. Epub 2012 Oct 17.

Abstract

Mutations in the gene encoding the iron-sulfur-containing DNA helicase DDX11 (ChlR1) were recently identified as a cause of a new recessive cohesinopathy, Warsaw breakage syndrome (WABS), in a single patient with severe microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Here, using homozygosity mapping in a Lebanese consanguineous family followed by exome sequencing, we identified a novel homozygous mutation (c.788G>A [p.R263Q]) in DDX11 in three affected siblings with severe intellectual disability and many of the congenital abnormalities reported in the WABS original case. Cultured lymphocytes from the patients showed increased mitomycin C-induced chromosomal breakage, as found in WABS. Biochemical studies of purified recombinant DDX11 indicated that the p.R263Q mutation impaired DDX11 helicase activity by perturbing its DNA binding and DNA-dependent ATP hydrolysis. Our findings thus confirm the involvement of DDX11 in WABS, describe its phenotypical spectrum, and provide novel insight into the structural requirement for DDX11 activity.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Amino Acid Sequence
  • Base Sequence
  • Chromosome Breakage
  • Consanguinity
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / metabolism
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • Exome / genetics
  • Family Health
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Intellectual Disability
  • Male
  • Mutation, Missense*
  • Pedigree
  • Sequence Analysis, DNA
  • Syndrome

Substances

  • DNA Helicases
  • DDX11 protein, human
  • DEAD-box RNA Helicases