RAG1 – Omenn syndrome

Omenn syndrome (OS) is a rare autosomal recessive immunodeficiency characterized by oligoclonal expansion of autoreactive T cells, erythroderma, hepatosplenomegaly, eosinophilia, and absence of B lymphocytes. Hypomorphic or null variants in RAG1 impair V(D)J recombination, leading to partial generation of T-cell receptors and failure of B-cell development (PMID:15845893).

RAG1-OS follows an autosomal recessive inheritance, confirmed by homozygous and compound heterozygous mutations in consanguineous families and unrelated probands across multiple studies. At least 37 probands have been described, with segregation of deleterious alleles in affected sibships and unaffected carriers (PMID:10606976).

The variant spectrum includes frameshift, nonsense, and missense mutations distributed throughout RAG1. Examples include c.2522G>A (p.Arg841Gln) in the catalytic core, c.519del (p.Glu174fs) in the N-terminal domain, and C325Y in the RING finger domain. Hypomorphic alleles retain residual recombinase activity (1–50%), correlating with OS, whereas null alleles result in T–B–SCID (PMID:11121059, PMID:18056378).

Functional studies demonstrate that hypomorphic RAG1 mutants exhibit reduced V(D)J recombination activity in cellular assays and altered histone H3 ubiquitylation by the RING domain. Knock-in murine models replicate lymphopenia, oligoclonal T cells, and predisposition to autoreactivity, confirming a loss-of-function mechanism with partial rescue by secondary mutations (PMID:24290284, PMID:20122409).

Somatic reversion mosaicism has been reported to modify the clinical phenotype, with second-site mutations restoring RAG1 reading frame and leading to OS in an initially SCID-predisposed patient (PMID:15845893, PMID:24817258).

Integrating genetic and mechanistic data, the RAG1–Omenn syndrome association is Definitive, supporting diagnostic genetic testing for RAG1 in patients with erythroderma, eosinophilia, and absent B cells. Early identification enables timely hematopoietic stem cell transplantation, improving survival.

References

• Clinical and experimental immunology • 2000 • Characterization of immune function and analysis of RAG gene mutations in Omenn syndrome and related disorders PMID:10606976
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains PMID:11121059
• Blood • 2005 • Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency PMID:15845893
• The Journal of allergy and clinical immunology • 2014 • A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency PMID:24290284
• Molecular cell • 2010 • The RING domain of RAG1 ubiquitylates histone H3: a novel activity in chromatin-mediated regulation of V(D)J joining PMID:20122409
• Journal of clinical immunology • 2014 • RAG1 reversion mosaicism in a patient with Omenn syndrome PMID:24817258

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