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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-01-0187.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1446-1452
IMMUNOBIOLOGY
Radiosensitive SCID patients with Artemis gene
mutations show a complete B-cell differentiation arrest at the
pre-B-cell receptor checkpoint in bone marrow
Jeroen G. Noordzij,
Nicole
S. Verkaik,
Mirjam van der
Burg,
Lieneke R. van Veelen,
Sandra de Bruin-Versteeg,
Wouter Wiegant,
Jaak M. J. J. Vossen,
Corry M. R. Weemaes,
Ronald de
Groot,
Malgorzata Z. Zdzienicka,
Dik C. van
Gent, and
Jacques J. M. van
Dongen
From the Department of Immunology, Erasmus
MC/University Medical Center Rotterdam, The Netherlands;
Department of Cell Biology and Genetics, Erasmus MC/University Medical
Center Rotterdam, The Netherlands; Department of
Pediatrics, Division of Immunology and Infectious Diseases, Erasmus
MC/University Medical Center Rotterdam, The Netherlands;
Department of Pediatrics, Leiden University Medical Center, The
Netherlands; Department of Pediatrics, University Medical Center
Nijmegen - St Radboud, The Netherlands; Department of
Radiation Genetics and Chemical Mutagenesis, Leiden University Medical
Center, The Netherlands; Department of Radiation Oncology,
Erasmus MC/University Medical Center Rotterdam, The
Netherlands; and Department of Molecular Cell Genetics, the
Ludwik Rydygier University of Medical Sciences, Bydgoszcz,
Poland.
Severe combined immunodeficiency disease (SCID) can be
immunologically classified by the absence or presence of T, B, and natural killer (NK) cells. About 30% of
T BNK+ SCID patients carry
mutations in the recombination activating genes (RAG). Some
TBNK+ SCID patients without
RAG gene mutations are sensitive to ionizing radiation, and several of these radiosensitive (RS) SCID patients were
recently shown to have large deletions or truncation mutations in the
Artemis gene, implying a role for Artemis in DNA
double-strand break (dsb) repair. We identified 5 RS-SCID patients
without RAG gene mutations, 4 of them with
Artemis gene mutations. One patient had a large genomic
deletion, but the other 3 patients carried simple missense mutations in
conserved amino acid residues in the SNM1 homology domain of the
Artemis protein. Extrachromosomal V(D)J recombination assays showed
normal and precise signal joint formation, but inefficient coding joint
formation in fibroblasts of these patients, which could be complemented
by the wild-type Artemis gene. The cells containing
the missense mutations in the SNM1 homology domain had the same
recombination phenotype as the cells with the large deletion,
indicating that these amino acid residues are indispensable for Artemis
function. Immunogenotyping and immunophenotyping of bone marrow samples
of 2 RS-SCID patients showed the absence of complete
VH-JH gene rearrangements and consequently a
complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint that is, at the transition from CyIgµ
pre-B-I cells to CyIgµ+ pre-B-II cells. The completeness
of this arrest illustrates the importance of Artemis at this stage of
lymphoid differentiation.
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