Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele.

Abstract

The human receptor for the complement cleavage fragments C3b and C4b (complement receptor type 1, CRl) is found on the surfaces of erythrocytes, most peripheral blood leukocytes, glomerular podocytes, and follicular dendritic cells, and in plasma (1-3). Besides the removal of C3b-or C4b-coated microorganisms or immune complexes (4), CRl also serves as an inhibitor of the C3 and the C5 convertases by dissociating C2b and Bb fragments and by acting as a cofactor for the factor I-mediated cleavage of C3b and C4b (5, 6) . This regulatory capacity is shared by the structurally related members of a supergene family, termed the regulator of complement activation (RCA)t region, located on chromosome 1 (7-13) .Human CRl is a single chain glycoprotein with four allotypic variants that differ in Mr on SDS-PAGE by increments of 40-50 kD (14-17). The two most common variants are termed F and S (or A and B allotypes) and exhibit Mr of 250 and 290 kD, respectively. These variations reflect differing lengths of the polypeptides and not posttranslational modifications, since distinct unglycosylated precursors have been described (18) and incremental differences of 1.3 to 1.5 kb were also observed in the CRl transcripts from various allotypes (19,20). The cDNA that encodes the entire F allotype of 2,039 amino acids (aa) has been sequenced and the extracellular portion of the molecule is found to comprise 30 short consensus repeats (SCR). A feature that distinguishes CR1 from the other proteins of this gene family is the organization of the NH2-terminal 28 SCRs into four tandem long homologous repeats (LHR) of about 450 aa, each containing seven SCRs . Extensive sequence homologies of 60 to 99% have been observed among the LHRs, suggesting that they have arisen by gene duplication (21,22).

Human gene copy number variation and infectious disease

“…We would also support 435 internationalisation of research -no country has a monopoly on methods or expertise, and 436 restricting sharing of data or resources impedes our understanding, to the detriment not only of the 437 researchers but of individuals with the disease. Nevertheless, we anticipate an exciting future for 438 studying host complex CNV and infectious disease susceptibility: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Complement complement receptor 1 (Wong et al 1989). 464…”

Genetics and Epigenetic in Systemic Lupus Erythematosus

“…The most frequent type of CR1 (F or A) is comprised of four extracellular LHRs and expresses one binding site for C4b and two binding sites for C3b (Wong, 1983). The S (or B) variant of CR1 is characterized by additional C3b binding site on a fifth LHR (Wong, 1989). A meta-analysis for the CR1 functional polymorphisms in SLE shows no significant association of CR1 L allele, L/L genotype, and L/L+L/H genotypes with SLE.…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…It is thought that the differences in the alleles arose from unequal crossover events during replication, that lead to deletions or duplications of the highly repetitive section of DNA encoding the LHR, such that the size difference between the alleles is equivalent to one LHR; around 18kb at the genetic level, and 1.4kb at the transcript level (Holers et al 1987;Wong et al 1989;. It is speculated that the crossover events resulting in the creation/deletion of the highly homologous LHRs occurred relatively recently in our evolutionary history, while duplication of the SCRs, which show looser conservation and are found throughout the RCA family, as well as other, noncomplement related proteins, arose through much older genetic events (Holers et al 1987).…”