A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation.
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.
van der Burg
Mirjam
M
Department of Immunology and Department of Cell Biology and Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
van Veelen
Lieneke R
LR
Verkaik
Nicole S
NS
Wiegant
Wouter W
WW
Hartwig
Nico G
NG
Barendregt
Barbara H
BH
Brugmans
Linda
L
Raams
Anja
A
Jaspers
Nicolaas G J
NG
Zdzienicka
Malgorzata Z
MZ
van Dongen
Jacques J M
JJ
van Gent
Dik C
DC
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*
C000607893:LIG4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP