Submitted September 6, 2007
Accepted October 29, 2007
The Modifier of Hemostasis (MH) locus on chromosome 4 controls in vivo hemostasis of Gp6-/- mice
Yann Cheli, Deborah Jensen, Patrizia Marchese, David Habart, Tim Wiltshire, Michael Cooke, Jose A. Fernandez, Jerry Ware, Zaverio M. Ruggeri, and Thomas J. Kunicki*
Roon Research Center for Arteriosclerosis & Thrombosis, Dept of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA
Genomics Institute of the Novartis Research Foundation, San Diego, CA
* Corresponding author; email: tomk{at}scripps.edu.
Platelet glycoprotein VI (GPVI) is a key receptor for collagens that mediates the propagation of platelet attachment and activation. Targeted disruption of the murine gene Gp6 on a mixed 129X1/SvJ x C57BL/6J background causes the expected defects in collagen-dependent platelet responses in vitro. The extent of this dysfunction in all Gp6-/- mice is uniform and is not affected by genetic background. However, the same Gp6-/- mice exhibit two diametrically apposed phenotypes in vivo. In some mice, tail bleeding times are extremely prolonged (LONG), and thrombus formation in an in vivo carotid artery ferric chloride-injury model is significantly impaired. In other littermates, tail bleeding times are within the range of wild-type mice (SHORT), and in vivo thrombus formation is indistinguishable from control mice. Directed intercrosses revealed that these phenotypes are heritable, and a genome wide SNP scan revealed the most significant linkage to a single locus (8 Mb) on chromosome 4 (LOD score = 6.9, p < 0.0001) that we designate Modifier of Hemostasis (MH). Our results indicate that one or more modifier genes in MH control the extent to which in vivo platelet thrombus formation is disrupted by the absence of platelet GPVI.
