The Modifier of hemostasis (Mh) locus on chromosome 4 controls in vivo hemostasis of Gp6-/- mice.
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 129 x 1/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 2 diametrically opposed phenotypes in vivo. In some mice, tail bleeding times are extremely prolonged, 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, and in vivo thrombus formation is indistinguishable from that of control mice. Directed intercrosses revealed that these phenotypes are heritable, and a genome-wide single-nucleotide polymorphism scan revealed the most significant linkage to a single locus (8 megabases) on chromosome 4 (logarithm of the odds [LOD] score = 6.9, P < .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.
Cheli
Yann
Y
Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Jensen
Deborah
D
Marchese
Patrizia
P
Habart
David
D
Wiltshire
Tim
T
Cooke
Michael
M
Fernandez
José A
JA
Ware
Jerry
J
Ruggeri
Zaverio M
ZM
Kunicki
Thomas J
TJ
D000818:Animals; D001158:Arteries / Q000293:injuries; D001760:Bleeding Time; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002875:Chromosomes / Q000235:genetics*; D016678:Genome / Q000235:genetics; D006487:Hemostasis; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI