title: A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation.
abstract: V(D)J recombination of Ig and TCR loci is a stepwise process during which site-specific DNA double-strand breaks (DSBs) are made by RAG1/RAG2, followed by DSB repair by nonhomologous end joining. Defects in V(D)J recombination result in SCID characterized by absence of mature B and T cells. A subset of T-B-NK+ SCID patients is sensitive to ionizing radiation, and the majority of these patients have mutations in Artemis. We present a patient with a new type of radiosensitive T-B-NK+ SCID with a defect in DNA ligase IV (LIG4). To date, LIG4 mutations have only been described in a radiosensitive leukemia patient and in 4 patients with a designated LIG4 syndrome, which is associated with chromosomal instability, pancytopenia, and developmental and growth delay. The patient described here shows that a LIG4 mutation can also cause T-B-NK+ SCID without developmental defects. The LIG4-deficient SCID patient had an incomplete but severe block in precursor B cell differentiation, resulting in extremely low levels of blood B cells. The residual D(H)-J(H) junctions showed extensive nucleotide deletions, apparently caused by prolonged exonuclease activity during the delayed D(H)-J(H) ligation process. In conclusion, different LIG4 mutations can result in either a developmental defect with minor immunological abnormalities or a SCID picture with normal development.
authors.affiliation: Department of Immunology and Department of Cell Biology and Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Lieneke R
authors.initials: LR
authors.lastname: van Veelen
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Verkaik
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Wiegant
authors.forename: Nico G
authors.initials: NG
authors.lastname: Hartwig
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Barendregt
authors.forename: Linda
authors.initials: L
authors.lastname: Brugmans
authors.forename: Anja
authors.initials: A
authors.lastname: Raams
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.forename: Malgorzata Z
authors.initials: MZ
authors.lastname: Zdzienicka
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D012016:Reference Values; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C000607893:LIG4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP