Modular variations of the human major histocompatibility complex class IIIgenes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module) - A mechanism for gene deletions and disease associations

The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an exc ellent marker for major histocompatibility complex disease associations. As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX modu le. Duplications of the RCCX modules occurred by the addition of genomic fr agments containing a long (L) or a short (S) C4 gene, a CYP21A or a CYP21B gene, and the gene fragments TNXA and RP2, Four major RCCX structures with bimodular L-L, bimodular LS, monomodular L, and monomodular S are present i n the Caucasian population. These modules are readily detectable by TaqI RF LPs, The RCCX modular variations appear to be a root cause for the acquisit ion of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adren al hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination break point region and sequence analyses yielded definitive proof for an unequal crossover between TNXA om a bimodular chromosome and TNXB from a monomodula r chromosome.