Burg, van der M. (Mirjam)Zdzienicka, M.Z. (Malgorzata)Gent, van D.C. (Dik)Dongen, van J.J.M. (Jacques)Veelen, van L.R.Verkaik, N.S. (Nicole)Wiegant, W.W. (Wouter)Hartwig, N.G. (Nico)Barendregt, B.H. (Barbara)Brugmans, L.J.L. (Linda)Raams, A. (Anja)Jaspers, N.G.J. (Nicolaas)AnimalsHumansResearch Support, Non-U.S. Gov'tMiceReference ValuesMutationMice, SCIDB-Lymphocytes/*immunologyT-Lymphocytes/*immunologyDNA Ligases/*geneticsSevere Combined Immunodeficiency/*genetics/*immunologyKiller Cells, Natural/*immunologyhttp://hdl.handle.net/1765/8414enjournalArticle0021-9738V(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.2006-01-01 0021-9738 urn:NBN:nl:ui:15-1765/8414