Genetic regulation of a structural polymorphism of human C3b receptor.

Abstract

A B S T R A C T Two forms of the human C3b receptor (C3bR), which have relative molecular weights (Mr) of 250,000 and 260,000 and are designated F and S, respectively, have been identified in specific immunoprecipitates from erythrocytes and leukocytes by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Both forms of the receptor were visualized on gels by autoradiography of 1251-labeled antigen and by silver nitrate staining. Individual donors expressed one of three possible patterns of C3bR, either the F or S form alone or both, and these patterns represented stable phenotypic characteristics of their erythrocytes and polymorphonuclear and mononuclear leukocytes. Removal of N-linked oligosaccharides by endoglycosidase-F treatment decreased the M, of both forms but did not abolish the difference in their electrophoretic mobilities. That both forms of the receptor were functional was indicated by the capacity of all antigenic C3bR sites on erythrocytes from individuals having any of the three phenotypes to bind dimeric C3b with affinities ranging from 3 to 5 X 107 M-l.Analyses of the occurrence of the F and S forms of C3bR in 76 individuals from 15 families revealed that this polymorphism was regulated by two alleles transmitted in an autosomal codominant manner. Of 111 normal unrelated individuals, 64.9% were homozygous for the F form (FF), 1.8% were homozygous for the S form (SS), and 33.3% were heterozygotes (FS). This distribution did not differ from that calculated by the Hardy-Weinberg equilibrium based on two codominant alleles that regulate the expression of the F and S forms and that have frequencies of 81.5 and 18.5%, After this work had been submitted, similar observations were reported independently (Dykman, T. R.,

Characterization of the human CR1 gene promoter

“…The human CR1 is a single chain membrane glycoprotein with four allotypic variants that differ in molecular weight (Mr) by increments of 40-50 kDa [3]. The reduced forms of CR1 exhibit 250,000 (CR1-A or F), 290,000 (CR1-B or S), 210,000 (CR1-C) and 320,000 Da (CR1-D).…”

“…The functions and expression levels of CRI, however, are likely to vary with the cell type on which it is expressed. Different levels of expression of each structural allotype of CR1 have been observed in erythrocytes of heterozygotic donors [3,5]. Although nucleated cells may exhibit a similar pattern of differential expression, the ratio is often less distinct [3], perhaps reflecting the continuing de novo biosynthetic capacities of these cell types and their capacities to respond to cytokines [6].…”

Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B lymphocytes and of CR1 on neutrophils of patients with systemic lupus erythematosus

“…The erythrocytes of many patients with systemic lupus erythematosus (SLE) have a relative deficiency of the C3b/C4b receptor (complement receptor type 1 [CRl]) (1-7), a polymorphic membrane protein of 160,000-260,000 M , (8)(9)(10). In normal individuals, the number of CRl on erythrocytes is genetically regulated (3,5,6).…”

Analysis of multiple restriction fragment length polymorphisms of the gene for the human complement receptor type I. Duplication of genomic sequences occurs in association with a high molecular mass receptor allotype.

“…10). The common polymorphism seen with Eco RI showed no linkage dysequilibrium with any of the other RFLPs despite cosegregating with the Bam HI polymorphism, and locating the site of 10 . Proposed scheme of evolution of the 10 common alleles of CR1 identified by the combination of different RFLPs.…”

“…The structural phenotypes of CRI of individual donors were assessed by immunoprecipitation of CRI protein from erythrocyte membranes by YZ-1 monoclonal anti-CRI coupled to Sepharose and analysis of the eluted samples by SDS-PAGE and silver staining (10,21).…”