RFXANK – MHC class II deficiency

RFXANK is a critical subunit of the RFX transcriptional complex required for HLA-D gene expression. Biallelic loss-of-function variants in RFXANK cause autosomal recessive MHC class II deficiency, characterized by absent HLA-DR expression on B cells, monocytes, and activated T cells and resulting in combined immunodeficiency (PMID:14574520). The disorder ranges from early fatal courses without hematopoietic stem cell transplantation (HSCT) to moderate phenotypes with residual MHC II expression.

Genetic evidence includes case reports of homozygous IVS4+5G>A (splice defect) and c.232C>T (p.Arg78Ter) variants in single patients (PMID:14574520; PMID:35065305). Multi-center cohorts identified >70 patients from 50 families in North Africa with the founder c.338-25_338del variant (PMID:10803838) and additional RFXANK mutations in 9 of 35 patients in Turkey (PMID:38996837). Segregation in 22 consanguineous families confirms autosomal recessive inheritance (PMID:23314770).

The variant spectrum comprises multiple splice-site mutations (e.g., c.338-25_338del), frameshifts (c.600del, p.Ser83LeufsTer6), nonsense alleles (c.232C>T, p.Arg78Ter; c.634C>T, p.Arg212Ter), and missense substitutions (c.362A>T, p.Asp121Val; experimental Y224A). The recurrent c.338-25_338del founder allele accounts for >75 % of North African cases (PMID:10803838).

Functional studies demonstrate that splice mutations and nonsense alleles abolish RFXANK transcript and protein levels, abrogating RFX complex formation and HLA-D promoter transactivation (PMID:12618906). Missense mutants D121V fail to bind RFXAP, while Y224A binds DNA but lacks transactivation capacity. Intron 4 splice defects yield a truncated protein with residual activity, correlating with moderate phenotypes (PMID:14574520).

Clinically, patients present with pneumonia, chronic or protracted diarrhea, failure to thrive, fever, vomiting, cough, and B lymphocytopenia. Severity correlates with residual MHC II expression; moderate cases survive beyond infancy, whereas severe forms require early HSCT. A Turkish cohort showed later onset and improved survival in RFXANK-mutant patients compared with other complementation groups (PMID:38996837).

References

• Immunogenetics • 2003 • Splicing defect in RFXANK results in a moderate combined immunodeficiency and long-duration clinical course. PMID:14574520
• Immunogenetics • 2000 • Founder effect for a 26-bp deletion in the RFXANK gene in North African major histocompatibility complex class II-deficient patients belonging to complementation group B. PMID:10803838
• Immunogenetics • 2003 • Novel mutations in the RFXANK gene: RFX complex containing in-vitro-generated RFXANK mutant binds the promoter without transactivating MHC II. PMID:12618906
• Journal of clinical immunology • 2013 • Clinical, immunological and genetic findings of a large tunisian series of major histocompatibility complex class II deficiency patients. PMID:23314770
• Clinical immunology (Orlando, Fla.) • 2022 • Lessons learned from the diagnostic work-up of a patient with the bare lymphocyte syndrome type II. PMID:35065305
• 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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