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

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

Author information

1
Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada.

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.

PMID:
23033317
PMCID:
PMC4599780
DOI:
10.1002/humu.22226
[Indexed for MEDLINE]
Free PMC Article
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