Omenn syndrome due to ARTEMIS mutations.
Omenn syndrome (OS) is characterized by severe combined immunodeficiency (SCID) associated with erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. In patients with OS, B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. Thus far, inherited hypomorphic mutations of the recombination activating genes 1 and 2 (RAG1/2) have been described in OS. We report on a first patient with clinical and immunologic features of OS caused by hypomorphic ARTEMIS mutations. The patient's T cells expressed alpha/beta receptors with an oligoclonal repertoire but normal V(D)J recombination coding joints. Sequencing of the ARTEMIS gene revealed a compound heterozygosity in this nonhomologous end-joining (NHEJ) factor, explaining the enhanced radiosensitivity of the patient's primary dermal fibroblasts. The maternal allele contained a null mutation within the active center, whereas the expression of the paternal allele with a start codon (AUG to ACG) mutation partially restored V(D)J recombination and ARTEMIS function in vivo and in vitro.
Ege
Markus
M
Department of Transfusion Medicine, University Children's Hospital, University Hospital Ulm, Helmholtzstrasse 10, D-89081 Ulm, Germany.
Ma
Yunmei
Y
Manfras
Burkhard
B
Kalwak
Krzysztof
K
Lu
Haihui
H
Lieber
Michael R
MR
Schwarz
Klaus
K
Pannicke
Ulrich
U
D018387:Codon, Initiator; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases; D005347:Fibroblasts / Q000528:radiation effects; D015329:Gene Rearrangement, T-Lymphocyte; D019672:Genes, T-Cell Receptor; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D016511:Severe Combined Immunodeficiency / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D012867:Skin / Q000473:pathology; D013577:Syndrome
D018387:Codon, Initiator; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; C426344:DCLRE1C protein, human; D004720:Endonucleases