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PLoS One. 2015 Apr 7;10(4):e0121489. doi: 10.1371/journal.pone.0121489. eCollection 2015.

Compound heterozygous mutation of Rag1 leading to Omenn syndrome.

Author information

1
Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, United States of America; Department of Biological Sciences, Wellesley College, 106 Central St., Wellesley, MA, 02481, United States of America.
2
Molecular Genetics Core Facility, Children's Hospital Boston, Boston, MA 02115, United States of America.
3
Department of Dermatology, Mie University, Graduate School of Medicine, Mie 514-8507, Japan.
4
Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States of America.
5
Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Boston Children's Hospital, Boston, MA 02115, United States of America.
6
Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, United States of America.
7
Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, United States of America.

Abstract

Omenn syndrome is a primary immunodeficiency disorder, featuring susceptibility to infections and autoreactive T cells and resulting from defective genomic rearrangement of genes for the T cell and B cell receptors. The most frequent etiologies are hypomorphic mutations in "non-core" regions of the Rag1 or Rag2 genes, the protein products of which are critical members of the cellular apparatus for V(D)J recombination. In this report, we describe an infant with Omenn syndrome with a previously unreported termination mutation (p.R142*) in Rag1 on one allele and a partially characterized substitution mutation (p.V779M) in a "core" region of the other Rag1 allele. Using a cellular recombination assay, we found that while the p.R142* mutation completely abolished V(D)J recombination activity, the p.V779M mutation conferred a severe, but not total, loss of V(D)J recombination activity. The recombination defect of the V779 mutant was not due to overall misfolding of Rag1, however, as this mutant supported wild-type levels of V(D)J cleavage. These findings provide insight into the role of this poorly understood region of Rag1 and support the role of Rag1 in a post-cleavage stage of recombination.

PMID:
25849362
PMCID:
PMC4388548
DOI:
10.1371/journal.pone.0121489
[Indexed for MEDLINE]
Free PMC Article

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