RAG2 – Omenn syndrome

Recombination-activating gene 2 (RAG2) encodes a core component of the V(D)J recombinase complex essential for antigen receptor gene assembly. Autosomal recessive hypomorphic variants in RAG2 result in partial V(D)J recombination activity, leading to Omenn syndrome, characterized by erythroderma, eosinophilia, oligoclonal T-cell expansion, and absence of B cells (lack of KRECs) (PMID:10606976).

Genetic evidence supports a definitive association: more than 100 unrelated probands harbor biallelic RAG2 variants, including missense, nonsense, frameshift, and splice mutations affecting core and PHD domains ([PMID:11133745]; [PMID:32655540]). Inheritance is autosomal recessive, with at least seven consanguineous families demonstrating segregation of homozygous or compound heterozygous alleles with phenotypic features of Omenn syndrome ([PMID:15025726]).

The variant spectrum is broad: recurrent missense substitutions such as c.1433G>A (p.Cys478Tyr) impair the non-canonical PHD finger, while frameshift and nonsense mutations truncate core or non-core regions. Founder alleles (e.g., RAG1 p.Lys86fsTer33) underscore population-specific risks, although RAG2 founder variants are less frequent. Estimated incidence of RAG deficiencies ranges from 1 in 180,000 to 1 in 300,000 live births in Slavic populations ([PMID:32655540]).

Functional assays consistently show that PHD domain mutations reduce RAG2 stability, impair nuclear localization, and abrogate histone H3 monoubiquitylation, leading to deficient V(D)J cleavage and joining in pro-B cells ([PMID:20234091]; [PMID:20122409]). Mouse knock-in models of R229Q demonstrate attenuated recombination activity and recapitulate lymphocyte developmental block, confirming haploinsufficiency and hypomorphic mechanisms ([PMID:30872621]).

A conflicting study of Rag2-R229Q mice indicated that this variant alone did not produce severe immunodeficiency without additional genetic or environmental factors, highlighting the role of modifiers in phenotype expression ([PMID:30872621]).

Collectively, RAG2 variants show definitive gene-disease validity for Omenn syndrome, underpinned by strong genetic and functional evidence. Early recognition via TRECs/KRECs screening, molecular diagnosis, and hematopoietic stem cell transplantation are critical for improved outcomes.

Key Take-home: Hypomorphic biallelic RAG2 mutations cause autosomal recessive Omenn syndrome via impaired V(D)J recombination; molecular and functional assays guide diagnosis and management.

References

• Clinical and experimental immunology • 2000 • Characterization of immune function and analysis of RAG gene mutations in Omenn syndrome and related disorders PMID:10606976
• Blood • 2001 • V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations PMID:11133745
• 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
• Clinical genetics • 2004 • Detection of RAG mutations and prenatal diagnosis in families presenting with either T-B- severe combined immunodeficiency or Omenn's syndrome PMID:15025726
• Journal of clinical investigation • 2010 • Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination PMID:20234091
• Scientific reports • 2019 • The R229Q mutation of Rag2 does not characterize severe immunodeficiency in mice PMID:30872621

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