The molecular genetics of components of complement

Area of Science:

• Immunogenetics
• Molecular Biology
• Genomics

Background:

• Significant progress in mapping genes for complement components, including C2, Factor B, and C4, within the Major Histocompatibility Complex (MHC).
• Identification of duplicated cytochrome P-450 21-hydroxylase genes adjacent to C4 genes.
• Association of specific MHC haplotypes with increased susceptibility to autoimmune diseases.

Purpose of the Study:

• To detail the chromosome allocation and gene structure of complement components.
• To investigate the structural basis of polymorphisms and functional differences in complement proteins.
• To explore sequence homologies between complement proteins and their binding interactions.

Main Methods:

• Gene mapping and chromosome allocation.
• Analysis of complete gene and cDNA sequences.
• Structural elucidation of protein polymorphisms.

Main Results:

• Six genes mapped to the MHC region, with haplotypes linked to disease susceptibility.
• Complete gene structure of Factor B solved; progress made on C2 and C4.
• Complex C4 polymorphism identified with over 50 allotypes and structural basis for activity differences.
• Linkage established for C4bp, CR1, and Factor H genes.
• Sequence homologies found between complement proteins (e.g., C2, Factor B) and C3b/C4b binding proteins.
• cDNA sequences of C3 and C4 provided insights into post-translational modifications.
• Homology shown between C3, C4, C5, alpha 2-macroglobulin, and pregnancy zone protein.

Conclusions:

• Molecular genetics of complement components is rapidly advancing.
• Established linkages and homologies provide a framework for classifying complex genetic data.
• Understanding complement gene structure and function is crucial for disease association studies.