Compound Heterozygous Mutation of Rag1 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.

Genetic Screening of the Patients with Primary Immunodeficiency by Whole-Exome Sequencing

“…The second one leads an amino acid change (glutamic acid to lysine) in the core domain of RAG1 which is essential for V(D)J recombination. 11,12 In patient 2, T-B-NK+ SCID, we found a novel, nonsense c.581C > A variant (CADD: 36) in RAG2 gene. The homozygous single-nucleotide variant leads a premature stop codon instead of serine at conserved amino acid position 194 (Fig.…”

“…2b). 11,12 This variant has not been published before. The second one leads an amino acid change (glutamic acid to lysine) in the core domain of RAG1 which is essential for V(D)J recombination.…”

Investigation of Genetic Defects in Severe Combined Immunodeficiency Patients from Turkey by Targeted Sequencing

“…The first missense variant causes an amino acid change of arginine to glycine. It affects the B1 basic domain of the protein which serves as binding site for the nuclear transport proteins . The second missense variant leads to an alanine‐to‐valine change which was in the nanomer DNA‐binding region of the protein , (Fig.…”

Novel Compound Heterozygous Mutations in RAG1 in a Patient with Cutaneous Lymphoproliferative Disease

“…c.256-257del and c.C1331T, in RAG1. Matthews et al (15) reported a boy with OS bearing compound heterozygous mutations of RAG1.…”