title: Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome.
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.
authors.affiliation: Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada.
authors.forename: José-Mario
authors.initials: JM
authors.lastname: Capo-Chichi
authors.forename: Sanjay Kumar
authors.initials: SK
authors.lastname: Bharti
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Sommers
authors.forename: Tony
authors.initials: T
authors.lastname: Yammine
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brosh
authors.forename: André
authors.initials: A
authors.lastname: Mégarbane
authors.forename: Zoha
authors.initials: Z
authors.lastname: Kibar
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D019457:Chromosome Breakage; D003241:Consanguinity; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D004265:DNA Helicases; C101830:DDX11 protein, human; D053487:DEAD-box RNA Helicases