A polymorphism in the type one complement receptor (CR1) involves an additional cysteine within the C3b/C4b binding
Daniel J Birmingham1, Fawzi Irshaid, Katherine F Gavit
1Division of Nephrology, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, United States. Dan.Birmingham@osumc.edu <Dan.Birmingham@osumc.edu>
Molecular Immunology
|May 1, 2007
Summary
A common CR1 gene variation introduces an extra cysteine, significantly reducing its binding ability to complement proteins C3b and C4b. This CR1 polymorphism does not appear to increase the risk for SLE or lupus nephritis.
Area of Science:
- Immunology
- Genetics
Background:
- The type one complement receptor (CR1) plays a crucial role in the immune system by binding complement proteins C3b and C4b.
- CR1's structure comprises repeating units called short consensus repeats (SCRs), each containing cysteines essential for function via disulfide bonds.
Purpose of the Study:
- To identify and characterize a CR1 single nucleotide polymorphism (1597C>T) associated with an additional cysteine residue (483R>C).
- To investigate the functional impact of this CR1 polymorphism on C3b and C4b binding.
- To assess the association of this CR1 polymorphism with Systemic Lupus Erythematosus (SLE) and lupus nephritis.
Main Methods:
- Identification of a CR1 single nucleotide polymorphism (1597C>T) leading to an amino acid change (483R>C) in SCR 8.
- Expression of CR1 constructs with and without the 483-C variation to assess C3b/C4b binding.
- Analysis of carrier frequencies in African American and Caucasian populations.
- Comparison of 483-C carrier status between SLE patients and healthy controls.
Main Results:
- The 483-C polymorphism was found in 6.3% of African Americans and 2.4% of Caucasians.
- Expression constructs with the 483-C residue showed over 80% reduction in binding to C3b, C3bi, and C4b compared to wild-type.
- Full-length CR1 from carriers also exhibited reduced C3b and C4b binding, with the effect modulated by the number of binding domains.
- Carrier status for 483-C was not found to be a risk factor for SLE or lupus nephritis in race-matched comparisons.
Conclusions:
- The identified CR1 polymorphism (483R>C) significantly impairs the binding of CR1 to key complement proteins.
- Despite the functional impact on complement binding, this CR1 variation is not associated with an increased risk for SLE or lupus nephritis.
- The precise physiological role of this CR1 polymorphism warrants further investigation.
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