Molecular genetics of the fourth component of human complement

Area of Science:

• Immunogenetics
• Molecular immunology
• Human genetics

Background:

• The fourth component of complement (C4) is encoded by two highly polymorphic genes, C4A and C4B, located in the human major histocompatibility complex.
• Certain C4 alleles, especially null alleles, are linked to increased susceptibility to autoimmune diseases.

Purpose of the Study:

• To investigate the structural and functional basis of C4 polymorphism.
• To understand the relationship between C4 protein variation and autoimmune disease susceptibility.

Main Methods:

• Analysis of C4 gene structure and protein products.
• Identification of amino acid substitutions responsible for functional differences between C4A and C4B.
• Correlation of C4 structural variations with autoimmune disease associations.

Main Results:

• C4A and C4B proteins, despite structural similarity, exhibit significant differences in covalent binding efficiency to antigens.
• Key amino acid substitutions, located in the C4d region of the alpha chain, are identified as the cause of these functional disparities.
• A significant proportion of null alleles result from deletions encompassing both C4 and adjacent steroid 21-hydroxylase genes.

Conclusions:

• The structural variations within C4 proteins, particularly near the covalent binding site, are directly implicated in the altered functional properties.
• These functional differences in C4 proteins provide a molecular basis for the observed association between C4 gene variants and susceptibility to autoimmune diseases.