Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in Caucasians: The load of RCCX genetic diversity on major histocompatibility complex-associated disease

The complement component C4 genes located in the major histocompatibility c omplex (MHC) class III region exhibit an unusually complex pattern of varia tions in gene number, gene size, and nucleotide polymorphism. Duplication o r deletion of a C4 gene always concurs with its neighboring genes serineith reonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tena scin (TNX), which together form a genetic unit termed the RCCX module. A de tailed molecular genetic analysis of C4A and C4B and RCCX modular arrangeme nts was correlated with immunochemical studies of C4A and C4B protein polym orphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures acco unt for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, pri marily due to gene deletions and homoexpression of C4A proteins, have a com bined frequency of 31.6%. This is probably the most common variation of gen e dosage and gene size in human genomes. The seven RCCX physical variants c reate a great repertoire of haplotypes and diploid combinations, and a hete rozygosity frequency of 69.4%. This phenomenon promotes the exchange of gen etic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leadin g to MHC-associated diseases. An analyses of the RCCX structures in 22 salt -losing, congenital adrenal hypeplasia patients revealed a significant incr ease in the monomodular structure with a long C4 gene linked to the pseudog ene CYP21A, and bimodular structures with two CYP21A, which are likely gene rated by recombinations between heterozygous RCCX length variants.