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.

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Keywords Animals, B-Lymphocytes/*immunology, DNA Ligases/*genetics, Humans, Killer Cells, Natural/*immunology, Mice, Mice, SCID, Mutation, Reference Values, Research Support, Non-U.S. Gov't, Severe Combined Immunodeficiency/*genetics/*immunology, T-Lymphocytes/*immunology
Persistent URL hdl.handle.net/1765/8414
Journal Journal of Clinical Investigation
van der Burg, M, Zdzienicka, M.Z, van Gent, D.C, van Dongen, J.J.M, van Veelen, L.R, Verkaik, N.S, … Jaspers, N.G.J. (2006). A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. Journal of Clinical Investigation. Retrieved from http://hdl.handle.net/1765/8414