Deficiencies of Human Complement Component C4a and C4b and Heterozygosity in Length Variants ofRP-C4-CYP21-TNX(Rccx) Modules in Caucasians

Abstract

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account 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, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic 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 leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

“…15 Former investigations have shed light on the existence of seven frequent and several rare RCCX variants with regard to the number and length of C4 genes involved. 2,10,15,19 Our results are consistent with previous data, but have also led to novel findings. We have proved the existence of both LLS and LSL (trimodule with two long (L) and one short (S) C4 gene in the designated order) structures, and also showed evidence that even those trimodular haplotypes can belong to a different structural variant that contains long and short RCCX segments in identical order and also carries the same number of both C4A and C4B genes.…”

“…Observed frequencies of C4A, C4B, C4(L) and C4(S) genes, as well as of haplotypes with zero or two CYP21A2 copies, were similar to literature data (Table 1). 2,15 RCCX modular variations in healthy Hungarian Caucasians Considering all C4 and CYP21 gene variations examined, 15 different RCCX structures could be detected (Figure 2 Figure 1. Trimodular RCCX structure with binding sites of long PCR primers used.…”

“…Characterization of RCCX variants Z Bánlaki et al occurrence of RCCX length variants was consistent with data obtained from literature (Table 1). 2,15 Monomodular variants contained either a long C4A or a short C4B gene. Among bimodular structures, the most prevalent one was A(L)-B(L), followed by A(L)-B(S) and A(L)-A(L).…”

“…The most common RCCX variant, a bimodular structure with a single C4A and a single C4B copy, is arranged in the gene order STK19-C4A-CYP21A1P-TNXA-STK19P-C4B-CYP21A2-TNXB from telomeric to centromeric. 2 Variations within the RCCX have long been studied with respect to their contribution to disease susceptibility. Dosage of C4A and C4B genes influences the corresponding serum protein concentrations and hemolytic activities.…”

“…9 Population studies regarding RCCX structural variations are traditionally carried out using Southern blot techniques, generally directed at the total number of long and short C4 genes in the haplotypes, length of the most telomeric RCCX module of each chromosome and total C4A and C4B copy numbers in the genome. 2,3,10,11 However, no systematic study describing precise localization of C4A and C4B genes has yet been published, nor has the exact order of long and short C4 genes in RCCX structures containing more than two modules ever been determined. Thus, detailed characterization of RCCX structural variants occurring in the healthy Caucasian population became our goal.…”