Compound heterozygous mutation of Rag1 leading to Omenn syndrome

• Published in: PloS one Vol. 10; no. 4; p. e0121489
• Main Authors: Matthews, Adam G W, Briggs, Christine E, Yamanaka, Keiichi, Small, Trudy N, Mooster, Jana L, Bonilla, Francisco A, Oettinger, Marjorie A, Butte, Manish J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.04.2015; Public Library of Science (PLoS)
• Subjects: Alleles; Amino Acid Substitution; Antigens; Autoimmunity; B cells; Child; Child, Preschool; Cleavage; Deoxyribonucleic acid; DNA; Etiology; Genes; Genetic aspects; Genetics; Genotype & phenotype; Health aspects; Heterozygote; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Hospitals; Humans; Immunology; Infant; Infant, Newborn; Laboratories; Lymphocytes; Lymphocytes T; Male; Molecular biology; Mutation; Mutation, Missense; Pediatrics; Primary immunodeficiencies; Proteins; Proteolysis; Receptors; Recombination, Genetic; Rheumatology; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - metabolism; T cell receptors; T cells; United States > US; Massachusetts
• DOI: 10.1371/journal.pone.0121489
• ISSN: 1932-6203

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.