RAG1 – Immunodeficiency Disease

RAG1 encodes a lymphoid‐specific endonuclease essential for V(D)J recombination in developing B and T cells. Biallelic loss‐of‐function or hypomorphic variants in RAG1 disrupt antigen receptor gene assembly, leading to autosomal recessive immunodeficiency phenotypes ranging from severe combined immunodeficiency to granulomatous immunodeficiency. The disease entity under review here is immunodeficiency disease, characterized clinically by hypogammaglobulinemia, lymphopenia, and recurrent infections.

Genetic evidence for RAG1 in immunodeficiency disease includes a report of a 13-year-old boy with myelodysplastic syndrome and secondary immunodeficiency due to somatic uniparental disomy unmasking a homozygous missense RAG1 variant c.2095C>T (p.Arg699Trp) in bone marrow (PMID:31503426). In a separate series, three unrelated girls presented with early‐onset immunodeficiency, granulomas, hypogammaglobulinemia, and lymphopenia; each was compound heterozygous for RAG1 variants including c.2924G>A (p.Arg975Gln) among others (PMID:18463379). Together, these four probands support a consistent recessive inheritance pattern (4 probands; PMID:31503426, PMID:18463379).

Segregation analysis across the three germline families showed that unaffected parents are heterozygous carriers, with no additional affected relatives reported. The inheritance mode is uniformly autosomal recessive, with full concordance between variant zygosity and clinical phenotype.

The variant spectrum comprises at least six pathogenic missense changes (e.g., p.Arg699Trp, p.Arg975Gln, p.Arg778Gln, p.Arg314Trp, p.Arg507Trp) and somatic uniparental homozygosity, as well as occasional frameshift/truncating alleles. Recurrent mutations such as c.2924G>A (p.Arg975Gln) have been observed across independent cohorts, consistent with mutational hotspots in the core catalytic domain.

Functional studies demonstrate that RAG1 mutations confer loss or reduction of V(D)J recombination activity. Extrachromosomal recombination assays of core‐domain missense mutations show 3–30% residual activity (PMID:18463379), whereas frameshift and stop codon alleles abolish activity. In RAG1 knockout rats generated by zinc-finger nucleases, complete absence of mature B cells and thymic hypoplasia recapitulate the human immunodeficiency phenotype (PMID:23136839).

Integration of genetic and experimental data yields a Definitive gene–disease association: multiple unrelated probands with biallelic RAG1 variants, consistent autosomal recessive segregation, and robust functional concordance. Key take-home: RAG1 sequencing should be prioritized in patients with early-onset immunodeficiency, hypogammaglobulinemia, and lymphocyte development arrest.

References

• Molecular genetics & genomic medicine • 2019 • A rare case of acquired immunodeficiency associated with myelodysplastic syndrome. PMID:31503426
• The New England journal of medicine • 2008 • An immunodeficiency disease with RAG mutations and granulomas. PMID:18463379
• Blood • 2002 • The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. PMID:12200379
• BMC immunology • 2012 • Zinc-finger nuclease mediated disruption of Rag1 in the LEW/Ztm rat. PMID:23136839

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