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Omenn syndrome due to ARTEMIS mutations
Markus Ege1, Yunmei Ma, Burkhard Manfras
1Department of Transfusion Medicine, University Children's Hospital, University Hospital Ulm, Helmholtzstrasse 10, D-89081 Ulm, Germany.
Blood
|February 26, 2005
Summary
Omenn syndrome, a severe combined immunodeficiency, can be caused by mutations in the ARTEMIS gene, not just RAG1/2. This finding expands the genetic understanding of this rare condition.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Omenn syndrome (OS) is a severe combined immunodeficiency (SCID) presenting with erythroderma, hepatosplenomegaly, lymphadenopathy, and alopecia.
- Patients exhibit absent B cells, normal to elevated T cells with restricted T-cell receptor (TCR) repertoires.
- Previously, hypomorphic mutations in recombination activating genes 1 and 2 (RAG1/2) were the known cause of inherited OS.
Observation:
- This study reports the first case of Omenn syndrome caused by hypomorphic mutations in the ARTEMIS gene.
- The patient displayed characteristic OS features, including activated T cells with an oligoclonal repertoire.
- ARTEMIS is a crucial nonhomologous end-joining (NHEJ) factor involved in V(D)J recombination.
Findings:
- The patient had compound heterozygous ARTEMIS mutations: a null mutation on the maternal allele and a start codon mutation on the paternal allele.
- These ARTEMIS mutations led to enhanced radiosensitivity in the patient's dermal fibroblasts.
- Partial restoration of V(D)J recombination and ARTEMIS function was observed in vitro and in vivo due to the paternal allele's partial function.
Implications:
- This discovery broadens the genetic spectrum of Omenn syndrome, identifying ARTEMIS as a novel causative gene.
- Understanding the role of ARTEMIS mutations provides new insights into SCID pathogenesis.
- This finding may guide future genetic diagnostics and therapeutic strategies for patients with Omenn syndrome.