A new type of radiosensitive T–B–NK+ severe combined immunodeficiency

J. Clin. Invest. 116:137-145 (2006). doi:10.1172/JCI26121.
Copyright ©2006 by the American Society for Clinical Investigation
Research Article

A new type of radiosensitive T–B–NK+ severe combined immunodeficiency caused by a LIG4 mutation
Mirjam van der Burg1, Lieneke R. van Veelen2,3, Nicole S. Verkaik2, Wouter W. Wiegant4, Nico G. Hartwig5, Barbara H. Barendregt1,5, Linda Brugmans2, Anja Raams2, Nicolaas G.J. Jaspers2, Malgorzata Z. Zdzienicka4,6, Jacques J.M. van Dongen1 and Dik C. van Gent2

1Department of Immunology and
2Department of Cell Biology and Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
3Department of Radiation Oncology, Erasmus Medical Center–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
4Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
5Department of Pediatrics, Division of Immunology and Infectious Diseases, Erasmus Medical Center–Sophia Children’s Hospital, Rotterdam, The Netherlands.
6Department of Molecular Cell Genetics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.

Address correspondence to: Dik C. van Gent, Department of Cell Biology and Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Dokter Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Phone: 31-10-4087932; Fax: 31-10-4089468; E-mail: d.vangent@erasmusmc.nl.

Received for publication June 30, 2005, and accepted in revised form October 18, 2005.

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.

Linkback URL: http://www.jci.org/cgi/content/short/116/1/137?rss=1

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