Molecular Genetics of the Human MHC Complement Gene Cluster

Abstract

The human major histocompatibility complex (MHC) complement gene cluster (MCGC) is a highly variable region that is characterized by polymorphisms, variations in gene size and gene number, and associations with diseases. Deficiencies in complement C2 are either due to abolition of C2 protein synthesis by mini-deletions that caused frameshift mutations, or blocked secretion of the C2 protein by single amino acid substitutions. One, two or three C4 genes may be present in a human MCGC haplotype and these genes may code for C4A, C4B, or both. Deficiencies of C4A or C4B proteins are attributed to the expression of identical C4 isotypes or allotypes from the C4 loci, the absence or deletion of a C4 gene, 2-bp insertion at exon 29 or 1-bp deletion at exon 20 that caused frameshift mutations. The C4 genes are either 21 or 14.6 kb in size due to the presence of endogenous retrovirus HERV-K(C4) in the intron 9 of long C4 genes. A deletion or duplication of a C4 gene is always accompanied by its neighboring genes, RP at the 5′ region, and CYP21 and TNX at the 3′ region. These four genes form a genetic unit termed the RCCX module. In an RCCX bimodular structure, the pseudogene CYP21A, and partially duplicated gene segments TNXA and RP2 are present between the two C4 loci. The RCCX modular variations in gene number and gene size contributed to unequal crossovers and exchanges of polymorphic sequences/mutations, resulting in the homogenization of C4 polymorphisms and acquisitions of deleterious mutations in RP1, C4A, C4B, CYP21B and TNXB genes. RD, SKI2W, DOM3Z and RP1 are the four novel genes found between Bf and C4. RD and Ski2w proteins may be related to RNA splicing, RNA turnover and regulation of translation. The functions of Dom3z and RP1 are being investigated. The complete genomic DNA sequence between C2 and TNX is now available. This should facilitate a complete documentation of polymorphisms, mutations and disease associations for the MCGC.

Association of MHC class-III gene polymorphisms with ER-positive breast cancer in Chinese Han population

“…The human class III region, spanning approximately 700 kb, contains 61 genes and is the most gene-dense region of the human genome (Xie et al, 2003). It is known for the complement component genes C4 factor B (BF) and C2, which encode subunit proteins for the C3 and C5 convertases, enzymes essential for the complement activation pathways of the humoral immune response (Yu, 1998;Milner and Campbell, 2001). This body of evidence indicates that genetic variants in the MHC class III region may be associated with malignant cancer.…”

Vaccination against encapsulated bacteria in hereditary C2 deficiency results in antibody response and opsonization due to antibody-dependent complement activation

“…Two principal variants of C2D have been described [4,5]. The predominant variant of C2D is type I (90%), which is caused by homozygosity for a 28-base pair deletion in the C2 gene resulting in a complete lack of C2…”

“…This C2 deficiency gene is usually part of the major histocompatibility complex (MHC) haplotype HLA-B18, S042, DR2 [4,5,6]. C2D is associated with autoimmune diseases such as systemic lupus erythematosus (SLE) and with an increased susceptibility to infections caused by encapsulated bacteria such as S. pneumoniae and Hib [2,3,7,8,9].…”

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)

“…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).…”

“…1). The complex organizations of the C4A and C4B genes, together with the extensive polymorphisms of the C4A and C4B proteins render C4 an excellent marker for MHC 1 -associated diseases (1,3). For instance, congenital adrenal hyperplasia (CAH) is mainly caused by mutations or deletions of CYP21B (4), and systemic lupus erythematosus is correlated with C4A deficiencies (5).…”