RFX5 – MHC class II deficiency

Major histocompatibility complex class II (MHC II) deficiency is a severe autosomal recessive immunodeficiency characterized by absent HLA-DR expression on antigen-presenting cells and profound CD4+ T-cell dysfunction. Patients typically present in infancy with failure to thrive, recurrent pneumonia, persistent diarrhea and life-threatening infections. The RFX5 gene encodes the largest subunit of the RFX transcription factor complex, which binds promoter X boxes of MHC II genes and is essential for their expression (PMID:9401005).

Initial mapping of RFX5 defects identified four unrelated patients with biallelic splice-site and truncating mutations, including c.715C>T (p.Arg239Ter), c.757+1G>A and c.55_56dup (p.Gly20fs), localizing the gene to chromosome 1q21 (PMID:9401005). These variants abrogate DNA-binding and transactivation of MHC II promoters, establishing loss-of-function as the pathogenic mechanism. Complementation of RFX5-deficient cell lines rescues MHC II expression, confirming gene causality (PMID:10586057).

Subsequent cohorts have expanded the variant spectrum. In a multicenter Turkish study of 35 patients, eight carried RFX5 mutations, underscoring its prevalence among regulatory gene defects (PMID:38996837). In Egyptian patients, three of ten individuals harbored RFX5 variants, notably c.116+1G>A and the recurrent c.715C>T (p.Arg239Ter), accounting for ~30% of cases and correlating with early-onset disease and diagnostic delay (PMID:30170160).

A recent infant case report described compound heterozygosity for c.757+1G>A and the novel splice-site variant c.353+6T>G in RFX5. Functional RT-PCR demonstrated intron retention and frameshifting, truncating the DNA-binding domain and confirming pathogenicity of c.353+6T>G (PMID:36276949).

Mechanistic studies have delineated a critical leucine-rich motif (62–LYLYLQL–68) in RFX5 required for promoter engagement. Mutagenesis of these residues ablates DNA binding and transactivation without affecting protein stability, further defining loss-of-function as the disease mechanism (PMID:10586057).

Integration of genetic and experimental data supports a definitive association between biallelic RFX5 loss-of-function variants and autosomal recessive MHC II deficiency. The identification of truncating and splice-site mutations across >16 probands in unrelated families, combined with functional rescue and DNA-binding assays, confirms RFX5 as an essential regulator of MHC II expression. Key take-home: Genetic testing for RFX5 should be prioritized in early-onset combined immunodeficiency with absent HLA-DR expression to guide diagnosis, genetic counseling, and prompt allogeneic hematopoietic stem cell transplantation.

References

• Human mutation • 1997 • Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency. PMID:9401005
• Journal of immunology • 1999 • Analysis of the defect in IFN-gamma induction of MHC class II genes in G1B cells: identification of a novel and functionally critical leucine-rich motif (62-LYLYLQL-68) in the regulatory factor X 5 transcription factor. PMID:10586057
• The journal of allergy and clinical immunology. In practice • 2019 • MHC-II Deficiency Among Egyptians: Novel Mutations and Unique Phenotypes. PMID:30170160
• Frontiers in genetics • 2022 • Case Report: Novel splicing mutations in RFX5 causing MHC class II deficiency. PMID:36276949
• The journal of allergy and clinical immunology. In practice • 2024 • MHC Class II Deficiency: Clinical, Immunological, and Genetic Insights in a Large Multicenter Cohort. PMID:38996837

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