Increased hepatic fibrinogen B beta-gene transcription is not enough to increase plasma fibrinogen levels - A transgenic mouse study

The fibrinogen A alpha, B beta, and gamma polypeptides are encoded by three separate genes. which are arranged in the order gamma-alpha-beta. In order to study the biosynthesis of fibrinogen in vivo we generated a line of tra nsgenic mice carrying extra copies of the fibrinogen beta -gene. To clone t he mouse fibrinogen B beta -chain gene, a mouse 129 Sv/Ev genomic cosmid li brary was screened, using the mouse fibrinogen A alpha-,B beta -chain cDNA. A clone containing the complete Fibrinogen B beta -chain gene including ap proximately 11-kb of the natural promoter region was identified and subsequ ently microinjected into mice. Southern blot analysis identified a founder that carried additional copies of the fibrinogen B beta -chain gene, Transg enic offspring of this founder were interbred and heterozygous and homozygo us transgenic mice were obtained. Northern blot analysis demonstrated appro ximately a 3-fold increase in fibrinogen B beta mRNA in heterozygous mice a s compared to wild-type, whereas homozygous transgenic mice showed approxim ately a 9-fold increase. The levels of the A alpha and gamma mRNAs in trans genic homozygous mice were not changed as compared to those in wild-type mi ce. Fibrinogen levels in plasma were not significantly increased in transge nic mice as compared to wild-type mice. These results indicate that: additi onal copies of the fibrinogen B beta -chain gene lead to increased levels o f the B beta -chain mRNA in the liver; the increased levels of B beta -chai n mRNA in homozygous overexpression mice do not change the transcription le vels of the two other fibrinogen mRNAs in vivo: the absence of an increased plasma fibrinogen level in the transgenic mice indicates that this level i s not regulated solely by transcription of the B beta -chain gene.