An allelic variant of Crry in the murine Sle1c lupus susceptibility interval is not impaired in its ability to regulate complement activation.
The Sle1c subinterval on distal murine chromosome 1 confers loss of tolerance to chromatin. Cr2, which encodes complement receptors 1 and 2 (CR1/CR2; CD35/CD21), is a strong candidate gene for lupus susceptibility within this interval based on structural and functional alterations in its protein products. CR1-related protein/gene Y (Crry) lies 10 kb from Cr2 and encodes a ubiquitously expressed complement regulatory protein that could also play a role in the pathogenesis of systemic lupus erythematosus. Crry derived from B6.Sle1c congenic mice migrated at a higher m.w. by SDS-PAGE compared with B6 Crry, as a result of differential glycosylation. A single-nucleotide polymorphism in the first short consensus repeat of Sle1c Crry introduced a novel N-linked glycosylation site likely responsible for this structural alteration. Five additional single-nucleotide polymorphisms in the signal peptide and short consensus repeat 1 of Sle1c Crry were identified. However, the cellular expression of B6 and B6.Sle1c Crry and their ability to regulate the classical pathway of complement were not significantly different. Although soluble Sle1c Crry regulated the alternative pathway of complement more efficiently than B6 Crry, as a membrane protein, it regulated the alternative pathway equivalently to B6 Crry. These data fail to provide evidence for a functional effect of the structural alterations in Sle1c Crry and suggest that the role of Cr2 in the Sle1c autoimmune phenotypes can be isolated in recombinant congenic mice containing both genes.
Tchepeleva
Svetlana N
SN
Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Thurman
Joshua M
JM
Ruff
Katherine
K
Perkins
Stephen J
SJ
Morel
Laurence
L
Boackle
Susan A
SA
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D003167:Complement Activation / Q000276:immunology*; D003170:Complement Pathway, Alternative / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D015151:Immunoblotting; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D011951:Receptors, Complement / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D017463:Receptors, Complement 3b
C081470:Cr1l protein, mouse; D011951:Receptors, Complement; D017463:Receptors, Complement 3b