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 DH-JH junctions showed extensive nucleotide deletions, apparently caused by prolonged exonuclease activity during the delayed DH-JH 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.
Mirjam van der Burg, Lieneke R. van Veelen, Nicole S. Verkaik, Wouter W. Wiegant, Nico G. Hartwig, Barbara H. Barendregt, Linda Brugmans, Anja Raams, Nicolaas G.J. Jaspers, Malgorzata Z. Zdzienicka, Jacques J.M. van Dongen, Dik C. van Gent
Clonogenic survival assay of fibroblasts after IR.