A NOVEL DNA-BINDING REGULATORY FACTOR IS MUTATED IN PRIMARY MHC CLASS-II DEFICIENCY (BARE LYMPHOCYTE SYNDROME)

Regulation of MHC class II gene expression is an essential aspect of t he control of the immune response. Primary MHC class II deficiency is a genetically heterogeneous disease of gene regulation that offers the unique opportunity of a genetic approach for the identification of th e functionally relevant regulatory genes and factors. Most patients ex hibit a characteristic defect in the binding of a nuclear complex, RFX , to the X box motif of MHC class II promoters. Genetic complementatio n of a B-lymphocyte cell line from such a patient-with a cDNA expressi on library has allowed us to isolate RFX5, the regulatory gene respons ible for the MHC class II deficiency. This gene encodes a novel DNA-bi nding protein that is indeed a subunit of the RFX complex. Mutations i n the RFX5 gene have been characterized in two patients. Transfection of the patient's cells with the RFX5 cDNA repairs the binding defect a nd fully restores expression of all the endogenous MHC class II genes in vivo.