RAG1 – Severe Combined Immunodeficiency

RAG1 encodes a lymphoid‐specific endonuclease essential for V(D)J recombination in developing B and T cells. Autosomal recessive loss‐of‐function or hypomorphic mutations in RAG1 lead to a T–B–NK+ form of severe combined immunodeficiency (SCID), characterized by absent circulating B cells and profound impairment of T‐cell repertoire assembly (PMID:11133745).

A landmark study of 44 unrelated patients from 41 families demonstrated that biallelic null mutations result in classical T–B–SCID, whereas at least one hypomorphic allele yields Omenn syndrome or leaky SCID phenotypes due to residual recombination activity (PMID:11133745). Segregation of homozygous or compound heterozygous RAG1 variants with disease was observed across consanguineous and nonconsanguineous kindreds, confirming autosomal recessive inheritance and complete penetrance in early infancy.

The variant spectrum comprises >60 distinct alleles, including truncating frameshift (e.g., c.256_257del (p.Lys86ValfsTer33)), nonsense (e.g., c.2320G>T (p.Glu774Ter)), and missense substitutions (e.g., p.Arg764His) that variably abrogate recombinase function. Recurrent founder alleles such as c.256_257del have been identified in Slavic populations, present in homozygous and compound heterozygous states in 47% of regional cases (PMID:32655540).

Functional assays demonstrate that null RAG1 proteins lack V(D)J cleavage and joint formation activity, whereas hypomorphic mutants retain partial recombination capability in vitro and in cellular models (PMID:11121059). Transgenic and knockin mouse models harboring hypomorphic alleles recapitulate defective lymphocyte development and genome instability, underscoring pathogenic mechanisms involving impaired coding‐end hairpin processing and postcleavage complex formation.

Beyond recombination defects, RAG1’s N‐terminal RING finger ubiquitin ligase domain mediates monoubiquitylation of histone H3, facilitating chromatin accessibility at antigen receptor loci; mutations disrupting this domain reduce histone ubiquitylation and chromosomal recombination efficiency (PMID:20122409).

Collectively, >100 affected individuals across >20 publications, robust segregation data, and concordant functional studies establish a definitive gene–disease relationship. Early genetic diagnosis of RAG1 deficiency guides timely hematopoietic stem cell transplantation, which remains the only curative therapy.

References

• Blood • 2001 • V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations PMID:11133745
• 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
• 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
• Frontiers in Immunology • 2020 • The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries PMID:32655540

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