The Gene Coding for the β-Chain of C4b-Binding Protein (C4BPB) Has Become a Pseudogene in the Mouse

C4BPβ is one of the two polypeptides that in humans compose the plasma glycoprotein C4b-binding protein (C4BP). C4BPβ binds the anticoagulant vitamin K-dependent protein S. Two, nonmutually exclusive, roles have been proposed for the C4BP-protein S interaction. It has been suggested to play a role in the control of the protein C anticoagulatory pathway. In addition, it may serve an important role in localizing C4BP to the surface of injured or activated cells. While the physiological significance of C4BP-protein S interaction is unclear, it has clinical relevance because elevated plasma levels of C4BP are associated with increased risk for thromboembolic disorders in humans, due to an inactivation of the protein C anticoagulatory pathway. Using a human C4BPβ cDNA probe, we have isolated and characterized a genomic DNA fragment that includes the murine C4BPB gene. Murine C4BPB is a single-copy gene that maps close to the C4BPA gene in chromosome 1. It contains two exons homologous to the exons coding for the SCR-1 and SCR-2 repeats of the human C4BPβ polypeptide chain. Sequence analysis of the C4BPB exons in the Mus musculus inbred strains CBA, Balb/c, and C57BL/6, in penbred Swiss mice, and in Mus spretus demonstrated the presence of two in-phase stop codons that are incompatible with the expression of a functional C4BPβ polypeptide. Thus, the characterization of the murine C4BPB gene documents the peculiar situation of a single-copy gene that is functional in humans but has become a pseudogene in the mouse. Interestingly, the loss of a functional C4BPB gene is a relatively recent event in the evolution of the mouse. In addition, our data indicate that this genetic change has been fixed in the mouse population, suggesting that those individuals lacking the C4BPβ polypeptide were conferred with some kind of selective advantage.