An unequal crossover between the RCCX modules of the human MHC leading to the presence of a CYP21B gene and a tenascin TNXB/TNXA-RP2 recombinant between C4A and C4B genes in a patient with juvenile rheumatoid arthritis.

Abstract

The RCCX module of the human MHC class III region is comprised of four genes arranged in tandem: RP, complement C4, steroid 21-hydroxylase (CYP21), and tenascin X (TNX). Variations in the number and genes of the RCCX modules may lead to genetic and/or autoimmune diseases. Restriction fragment length polymorphism (RFLP) analysis was utilized to determine the RCCX modular variation in patients with juvenile rheumatoid arthritis (JRA). In JRA patient L1, RFLP analysis suggested the presence of a bimodular RCCX structure containing both C4A long and C4B short genes, yet missing the markers for the CYP21A and TNXA genes usually located between the C4A and C4B genes. The 7.5-kb genomic fragment spanning the CYP21-TNX-RP2 genes was cloned and sequenced, revealing that a genetic recombination occurred between TNXA of a bimodular RCCX chromosome and TNXB of a monomodular RCCX chromosome. This recombination results in a new MHC haplotype with a CYP21B gene and a TNXB/TNXA-RP2 recombinant between the two C4 genes. Elucidation of the breakpoint region provides further evidence for the instability of the MHC class III gene region as a result of the RCCX modular variation.