Compound heterozygous mutation of Rag1 leading to omenn syndrome leading to omenn syndrome Journal Article

Authors: Matthews, A. G. W.; Briggs, C. E.; Yamanaka, K.; Small, T. N.; Mooster, J. L.; Bonilla, F. A.; Oettinger, M. A.; Butte, M. J.
Article Title: Compound heterozygous mutation of Rag1 leading to omenn syndrome leading to omenn syndrome
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. © 2015 Matthews et al.
Keywords: child; gene mutation; human cell; busulfan; clinical feature; case report; follow up; allele; amino acid substitution; mucosa inflammation; cyclophosphamide; steroid; hematopoietic stem cell transplantation; in vitro study; mutational analysis; heterozygote; rash; chronic graft versus host disease; disease severity; graft rejection; protein folding; rag1 protein; rag2 protein; immunosuppressive treatment; cyclosporin a; nonsense mutation; alemtuzumab; protein cleavage; artificial ventilation; myositis; vdj recombination; human; article; omenn syndrome; rag1 gene; rag2 gene
Journal Title: PLoS ONE
Volume: 10
Issue: 4
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2015-04-07
Start Page: e0121489
Language: English
DOI: 10.1371/journal.pone.0121489
PROVIDER: scopus
PMCID: PMC4388548
PUBMED: 25849362
Notes: Export Date: 3 June 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Trudy Small
    215 Small