Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system

Abstract

C1r and C1s are the serine proteases that form the catalytic unit of the C1 complex, the first component of complement. In the present study, we found that the genes encoding murine C1r and C1s are duplicated. One set of these genes, referred to as c1rA and c1sA, are primarily expressed in the liver and are therefore the homologues of the human C1r and C1s genes. The other two genes, termed c1rB and c1sB, are expressed exclusively in male reproductive tissues, specifically the coagulating gland and the prostate. The predicted C1rB and C1sB proteins share 96 and 93% amino acid identity with C1rA and C1sA respectively. Most of the substitutions are clustered in the serine protease domains, suggesting differences in catalytic efficiencies and/or substrate specificities or alternatively adaptation to different physiological environments. The high homology of C1rB and C1sB with C1rA and C1sA in the non-catalytic regions indicates that they are probably capable of assembling the C1 complex. The expression of alternative genes encoding isomorphs of activating components of complement in male reproductive tissues raises the possibility of new mechanisms of complement activation in the male genital tract or of novel functions for complement proteases in reproduction.

CD59a Is the Primary Regulator of Membrane Attack Complex Assembly in the Mouse

“…CD59 is not alone among C proteins in being genetically duplicated in the mouse. The genes encoding DAF, C1r, and C1s are also duplicated, with expression of one form being confined to the reproductive organs (21,22). Our early studies examining the expression at the protein level of CD59b in wt and CD59a Ϫ/Ϫ mice were in accord with the mRNA findings and confirmed that CD59b expression was restricted to the testis (23).…”

“…The recent availability of mice in which individual C regulators have been deleted by homologous recombination has provided a powerful tool for examining the roles of the C regulators in various organs and contexts, but the analysis has been complicated by differences in C regulation between mouse and man. Mice possess additional regulators absent in man, modified regulators with distinct functions and duplicated regulators with differential tissue expression (18,21,22). CD59 falls into this last category with gene duplication giving rise to two CD59 proteins, both of which have the capacity to regulate C when expressed either on cells or as soluble molecules (20,23).…”

Inoprotection: The Perioperative Role of Levosimendan

“…Mitochondrial K ATP channels appear to be pivotal in ischaemic preconditioning, and specific mitochondrial channel openers have been proposed as the mechanism for cardioprotection during surgery [100][101][102] . Pharmacological activators of K ATP channels include levosimendan, nicorandil, cromakalim, diazoxide, minoxidil and pinacidil, while glibenclamide and tolbutamide both inhibit K ATP channels non-specifically.…”

A Genomic Analysis of Rat Proteases and Protease Inhibitors

“…In addition, and in contrast to the situation in the mouse genome, we have not found evidence of duplication of complement factors C1r and C1s in the rat genome. One set of these murine factors (c1rA and c1sA) are orthologs of the rat and human genes, whereas the others (c1rB and c1sB) are exclusively expressed in the male genital tract, indicating a role for these proteases in reproduction independent of complement activation (Garnier et al 2003). We have also found the presence in the rat genome of a nonprotease homolog called Ppnx, located in the X-inactivation center region (Xic) and strongly expressed in testis and undifferentiated ES cells (Chureau et al 2002).…”