MUTATION OF RFXAP, A REGULATOR OF MHC CLASS-II GENES, IN PRIMARY MHC CLASS-II DEFICIENCY

Background Major-histocompatibility - complex (MHC) class II deficienc y is an autosomal recessive primary immunodeficiency disease in which MHC class II molecules are absent, It is a genetically heterogeneous d isease of gene regulation resulting from defects in several transactiv ating genes that regulate the expression of MHC class II genes, The mu tations responsible for MHC class II deficiency are classified accordi ng to complementation group (a group in which the phenotype remains un corrected in pairwise fusions of cells), There are three known complem entation groups (A, B, and C). Methods To elucidate the genetic defect in patients with MHC class II deficiency that was not classified gene tically, we performed direct complementation assays with the three gen es known to regulate the expression of MHC class II genes, CIITA, RFX5 , and RFXAP, and the relevant mutations were identified in each patien t. Results Mutations in the RFXAP gene were found in three patients fr om unrelated families, and the resulting defect was classified as belo nging to a novel complementation group (D), Transfection with the wild -type RFXAP gene restored the expression of MHC class II molecules in the patients' cells. Conclusions Mutations in a novel MHC class II tra nsactivating factor, RFXAP, can cause MHC class II deficiency. These m utations abolish the expression of MHC class II genes and lead to the same clinical picture of immunodeficiency as in patients with mutation s in the other two MHC class II regulatory genes. (C) 1997, Massachuse tts Medical Society.