Modular Variations of the Human Major Histocompatibility Complex Class III Genes for Serine/Threonine Kinase RP, Complement Component C4, Steroid 21-Hydroxylase CYP21, and Tenascin TNX (the RCCX Module)

Abstract

The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an excellent 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 module. Duplications of the RCCX modules occurred by the addition of genomic fragments 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 L-S, monomodular L, and monomodular S are present in the Caucasian population. These modules are readily detectable by TaqI RFLPs. The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adrenal hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination breakpoint region and sequence analyses yielded definitive proof for an unequal crossover between TNXA from a bimodular chromosome and TNXB from a monomodular chromosome.Besides the immunoglobulins, complement component C4 is probably the most polymorphic serum protein. There are two isotypes, C4A and C4B, that manifest remarkable differences in chemical reactivities and serological properties (reviewed in Ref. 1). More than 34 allotypes for C4A and C4B have been demonstrated by agarose gel electrophoresis, based on gross differences in electric charge (2). Similar to the protein, the complement C4 genes are unusually complex with frequent variations in gene size and gene number. In addition, the genes surrounding C4A or C4B also exhibit considerable variations. These neighboring genes include RP1 or RP2 at the 5Ј region, CYP21A, or CYP21B and TNXA or TNXB at the 3Ј region ( Fig.

Complement genetics, deficiencies, and disease associations

“…In this cluster, two genes encoding human complement C4 protein (C4A and C4B) together with the serine/threonine nuclear kinase gene RP, the steroid 21-hydroxylase CYP21, and the extracellular matrix protein tenascin X (TNX) form a genetic unit: the RP-C4-CYP21-TNX (RCCX) module (Yang et al, 1999). The presence of a duplicated RCCX module has given rise to a complex structural polymorphism involving segmental deletions and duplications of the isotypic C4A and C4B genes, which is the major cause of genetic C4 deficiency.…”

Joint hypermobility syndromes: The pathophysiologic role of tenascin‐X gene defects

“…This region is highly susceptible to recombination events, leading to diverse diseases; for example, systemic lupus erythematosus is a consequence of C4A deficiency, IgA deficiency is caused by C4 mutations, and deficiency of Cyp21B results in congenital adrenal hyperplasia (CAH). Deletions of Cyp21B are known to extend into the tenascin-X gene in 1 of every 10 patients with CAH, creating a fusion gene (55,56). This results in a complete deletion of Cyp21B and a 120-bp deletion in the tenascin-X gene, truncating the open-reading frame (Figure 1).…”

“…Eighty patients, 90% of whom were female, were recruited from the Dutch EDS patient organization, and all were diagnosed by a medical specialist as having HT-EDS. Using the screening assay to detect tenascin-X in serum, 6 of these patients (7.5%) were identified with serum tenascin-X levels Ͼ2.5 standard deviations below the mean for normal individuals (100 Ϯ 14%), caused by either truncating mutations or low expressivity of the gene (56). Interestingly, the occurrence of tenascin-X haploinsufficiency in a Dutch population of patients diagnosed with BJHS (recruited from the BJHS patient organization) appears similar (5-10%) to that found in patients diagnosed with HT-EDS (Zweers MC, et al: unpublished observations).…”

The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes

“…Oligonucleotides of human C4 and RCCX constituents were designed based on published DNA sequences (51)(52)(53) 1,3,4,5,6,8,9,10,11,12,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,31,32,33,34,35,37,38,39,40, and 41. The primers were designed based on the genomic DNA sequence of C4A3a (51).…”

“…In other words, the number of C4 genes present in the class III region of the MHC on each copy of the chromosome 6 varies between one and four among different individuals (1,2). Duplication, triplication, and quadruplication of C4 genes are always concurrent with the neighboring genes RP at the 5Ј region and CYP21 and TNX at the 3Ј region (3)(4)(5). This discrete duplication unit is known as an RCCX 3 module.…”