Membrane and secretory forms of mouse membrane cofactor protein (CD46) generated from a single gene through alternative splicing

A cDNA encoding a new secretory form of mouse membrane cofactor protein (MC P, CD46) was identified additionally to the membrane form cDNA, The secreto ry MCP, predicted from the cDNA sequence, consisted of the conserved four s hort consensus repeats (SCRs) plus a four amino acid-stretch. Un like human MCP which comprises many isoforms, mouse MCP cDNA predicted a single isofo rm of membrane MCP with cytoplasmic tail 1 (CYT1) and serine/threonine-rich domain C (STC). To clarify the genomic origin and monomorphic alteration o f these cDNAs, we cloned and analyzed a mouse genomic DNA harboring the ful l coding sequence of MCP from a 129/SV mouse genomic library. The mouse Mcp was a single gene similar to 50 kilobases long. Eleven of the 14 coding ex ons of the human MCP gene and intron-exon boundary sequences were found to be conserved in the mouse gene. The STC homologue but not the STA or STB ho mologue in the mouse exons was functional: the latter being due to deletion s and lack of consensus sequences for splicing. The sequence equivalent to cytoplasmic tail 2 (CYT2) has not been identified in the Mcp genome, Thus, the three exons (STA, STB, and probably CYT2) responsible for the polymorph ism of human MCP by differential splicing were missing in the mouse Mcp gen e. Unlike the case in humans, no Mcp-related genes or pseudogenes were obse rved in the mouse genome. The single mouse Mcp gene was mapped to the R-pos itive H5 band of mouse Chromosome 1 by FISH. Strikingly, one alternative ex on with 73 base pairs (encoding the four new amino acids and a TGA stop cod on) was discovered between the SCRIV and the STC exons; alternative splicin g causes the generation of the secretory form of mouse MCP. These results o n mouse MCP, together with the information concerning other mouse SCR prote ins, infer that the regulator of complement activation (RCA) gene cluster i s genetically diverged between humans and mice.