RFXAP – MHC Class II Deficiency

MHC class II deficiency is an autosomal recessive combined immunodeficiency characterized by absent HLA class II expression on antigen‐presenting cells. Defects in trans‐acting regulatory factors, including RFXAP, underlie complementation group D, distinguishing it from groups A–C ([PMID:9442397]).

Biallelic loss‐of‐function variants in RFXAP have been identified in at least eight unrelated families and three additional patients, defining a strong genetic link to MHC class II deficiency ([PMID:9536093], [PMID:9287230]). Reported variants are predominantly nonsense and frameshift alleles, e.g., c.127C>T (p.Gln43Ter), leading to truncated RFXAP and loss of transactivation capacity.

Segregation analysis across multiple affected kindreds demonstrates autosomal recessive inheritance, with homozygous or compound heterozygous RFXAP variants co-segregating with disease phenotype in each family ([PMID:9536093]).

Functional complementation in deficient cell lines restores MHC class II expression upon transfection with wild‐type RFXAP cDNA, confirming the critical role of RFXAP in the RFX transcriptional complex ([PMID:9118943], [PMID:9442397]).

Mechanistically, RFXAP deficiency impairs assembly of the RFX multiprotein complex at promoters of HLA‐DR, ‐DQ, and ‐DP genes, abrogating transcriptional activation and resulting in profound immunodeficiency.

Together, these data support a Strong gene–disease association for RFXAP with MHC class II deficiency, with robust genetic evidence and concordant functional assays. Molecular diagnosis of RFXAP variants enables definitive classification of complementation group D and guides timely therapeutic interventions such as hematopoietic stem cell transplantation.

References

• Immunobiology • 1997 • MHC class II deficiency: definition of a new complementation group. PMID:9442397
• Human molecular genetics • 1998 • Genetic and molecular definition of complementation group D in MHC class II deficiency. PMID:9536093
• The EMBO journal • 1997 • RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. PMID:9118943
• The New England journal of medicine • 1997 • Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency. PMID:9287230

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