Omenn syndrome due to ARTEMIS mutations

Markus Ege, Yunmei Ma, Burkhard Manfras, Krzysztof Kalwak, Haihui Lu, Michael R Lieber, Klaus Schwarz, Ulrich Pannicke
Blood 2005 June 1, 105 (11): 4179-86
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.

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