Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene.
Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or approximately 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.
Lemmerhirt
Heidi L
HL
Howard Hughes Medical Institute, University of Michigan, 210 Washtenaw, Life Sciences Institute, Rm 5028, Ann Arbor, MI 48109, USA.
Shavit
Jordan A
JA
Levy
Gallia G
GG
Cole
Suzanne M
SM
Long
Jeffrey C
JC
Ginsburg
David
D
D019943:Amino Acid Substitution; D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D014644:Genetic Variation; D051379:Mice; D008815:Mice, Inbred Strains; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D011994:Recombinant Proteins; D014841:von Willebrand Factor