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The effect of null C4 alleles on complement function
Insights
The complement component C4 (C4) has common unexpressed alleles (nulls). Studies suggest null C4 genes do not significantly impair complement function, but may link to diseases via HLA haplotypes.
Area of Science:
- Immunogenetics
- Complement System Biology
Background:
- Complement component 4 (C4) is encoded by polymorphic C4A and C4B genes.
- Unexpressed alleles, termed 'nulls', are common and have been linked to various diseases.
Purpose of the Study:
- To investigate the functional impact of C4 null alleles.
- To explore potential mechanisms linking C4 null genes to disease susceptibility.
Main Methods:
- Assessed C4 allotypes and hemolytic efficiencies in 75 healthy individuals.
- Quantified C4 antigenic levels and in vitro C3 convertase formation kinetics.
Main Results:
- Mean C4 levels correlated with gene product number, but with significant individual variation.
- Homozygous C4A null individuals showed higher hemolytic efficiency; C4B null individuals showed lower efficiency compared to those with four gene products.
- No differences in C3 convertase formation kinetics were observed between C4A or C4B homozygous null individuals.
Conclusions:
- Null C4 genes do not appear to compromise overall complement function sufficiently to explain disease associations.
- Disease associations may arise from genetic linkage between C4 null alleles and susceptibility genes within extended HLA haplotypes.
Abstract:
C4 is encoded at two polymorphic genetic loci (C4A and B), and "null" or unexpressed alleles are relatively common. An increased frequency of nulls has been reported in a variety of diseases. In the present study, C4 allotypes and C4 hemolytic efficiencies (the ratios of functional to antigenic levels) were determined for a population of 75 normal unrelated individuals. Of these, 28 had three gene products (single null at C4A or B) while three had no expressed C4A products and three had no C4B products (homozygous null). Mean antigenic C4 levels correlated with the number of expressed gene products but there was a wide spread of individual values. Those homozygous null for C4A had greater, and for C4B less, hemolytic efficiency than those with four gene products. However, there was no difference in the in vitro kinetics of C3 convertase formation between homozygous null C4A or C4B individuals. Therefore, the presence of null genes for C4 does not appear to compromise complement function sufficiently to account for the reported disease associations. Some of the associations may result from the fact that null genes for C4, as part of an extended HLA haplotype, may be genetically linked to disease susceptibility.