title: A novel radiosensitive SCID patient with a pronounced G(2)/M sensitivity.
abstract: V(D)J rearrangement in lymphoid cells involves repair of double-strand breaks (DSBs) through non-homologous end joining (NHEJ). Defects in this process lead to increased radiosensitivity and severe combined immunodeficiency (RS-SCID). Here, a SCID patient, M3, is described with a T(-)B(+)NK(+) phenotype but without causative mutations in CD3delta, epsilon, zeta or IL7Ralpha, genes specifically involved in T cell development. Clonogenic survival of M3 fibroblasts showed an increased sensitivity to the DSB-inducing agents ionizing radiation and bleomycin, as well as the crosslinking compound, mitomycin C. We did not observe inactivating mutations in known NHEJ genes and results of various DSB-repair assays in G(1) M3 cells were indistinguishable from those obtained with normal cells. However, we found increased chromosomal radiosensitivity at the G(2) phase of the cell cycle. Checkpoint analysis indicated functional G(1)/S and intra-S checkpoints after irradiation but impaired activation of the "early" G(2)/M checkpoint. Together these results indicate a novel class of RS-SCID patients characterized by the specific absence of T lymphocytes and associated with defects in G(2)-specific DSB repair. The pronounced G(2)/M radiosensitivity of the RS-SCID patient described here, suggests a defect in a putative novel and uncharacterized factor involved in cellular DNA damage responses and T cell development.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Wiegant
authors.forename: Matty
authors.initials: M
authors.lastname: Meyers
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Verkaik
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Firouz
authors.initials: F
authors.lastname: Darroudi
authors.forename: Ron
authors.initials: R
authors.lastname: Romeijn
authors.forename: Ewa
authors.initials: E
authors.lastname: Bernatowska
authors.forename: Beata
authors.initials: B
authors.lastname: Wolska-Kusnierz
authors.forename: Bozena
authors.initials: B
authors.lastname: Mikoluc
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.forename: Cees
authors.initials: C
authors.lastname: Vreeken
authors.forename: Hanna
authors.initials: H
authors.lastname: Ijspeert
authors.forename: Rebecca E E
authors.initials: RE
authors.lastname: Esveldt-van Lange
authors.forename: Anna A
authors.initials: AA
authors.lastname: Friedl
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.forename: Albert
authors.initials: A
authors.lastname: Pastink
authors.forename: Małgorzata Z
authors.initials: MZ
authors.lastname: Zdzienicka
mesh_terms: D002455:Cell Division / Q000528:radiation effects*; D002460:Cell Line; D004249:DNA Damage; D016195:G2 Phase / Q000528:radiation effects*; D015321:Gene Rearrangement; D006801:Humans; D011836:Radiation Tolerance / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism; D045567:VDJ Recombinases / Q000235:genetics / Q000378:metabolism
chemical_list: D045567:VDJ Recombinases