Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly.
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.
Buck
Dietke
D
INSERM, Hôpital Necker-Enfants Malades, U768 Unité Développement Normal et Pathologique du Système Immunitaire, Paris, France.
Malivert
Laurent
L
de Chasseval
Régina
R
Barraud
Anne
A
Fondanèche
Marie-Claude
MC
Sanal
Ozden
O
Plebani
Alessandro
A
Stéphan
Jean-Louis
JL
Hufnagel
Markus
M
le Deist
Françoise
F
Fischer
Alain
A
Durandy
Anne
A
de Villartay
Jean-Pierre
JP
Revy
Patrick
P
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
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; C508551:NHEJ1 protein, human; D045643:DNA Repair Enzymes