title: Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly.
abstract: DNA double-strand breaks (DSBs) occur at random upon genotoxic stresses and represent obligatory intermediates during physiological DNA rearrangement events such as the V(D)J recombination in the immune system. DSBs, which are among the most toxic DNA lesions, are preferentially repaired by the nonhomologous end-joining (NHEJ) pathway in higher eukaryotes. Failure to properly repair DSBs results in genetic instability, developmental delay, and various forms of immunodeficiency. Here we describe five patients with growth retardation, microcephaly, and immunodeficiency characterized by a profound T+B lymphocytopenia. An increased cellular sensitivity to ionizing radiation, a defective V(D)J recombination, and an impaired DNA-end ligation process both in vivo and in vitro are indicative of a general DNA repair defect in these patients. All five patients carry mutations in the Cernunnos gene, which was identified through cDNA functional complementation cloning. Cernunnos/XLF represents a novel DNA repair factor essential for the NHEJ pathway.
authors.affiliation: INSERM, Hôpital Necker-Enfants Malades, U768 Unité Développement Normal et Pathologique du Système Immunitaire, Paris, France.
authors.forename: Dietke
authors.initials: D
authors.lastname: Buck
authors.forename: Laurent
authors.initials: L
authors.lastname: Malivert
authors.forename: Régina
authors.initials: R
authors.lastname: de Chasseval
authors.forename: Anne
authors.initials: A
authors.lastname: Barraud
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fondanèche
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Stéphan
authors.forename: Markus
authors.initials: M
authors.lastname: Hufnagel
authors.forename: Françoise
authors.initials: F
authors.lastname: le Deist
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
mesh_terms: D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002453:Cell Cycle / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D045643:DNA Repair Enzymes; D049914:DNA Repair-Deficiency Disorders / Q000150:complications / Q000235:genetics* / Q000276:immunology; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000276:immunology / Q000528:radiation effects; D015322:Gene Rearrangement, B-Lymphocyte; D006130:Growth Disorders / Q000150:complications / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008231:Lymphopenia / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008831:Microcephaly / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D011836:Radiation Tolerance / Q000235:genetics; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; C508551:NHEJ1 protein, human; D045643:DNA Repair Enzymes