International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 74 - CHARACTERIZATION OF THE REGULATORY MUTATION MVWF1, A MAJOR CAUSE OF PROLONGED APTTS IN MICE.

Johnsen J 1, Ginsburg D2

1 University of Michigan, Ann Arbor, United States, 2 Howard Hughes Medical Institute, Ann Arbor, United States

We previously identified a modifier gene, Mvwf1, as the cause of low levels of von Willebrand factor (VWF) in the inbred mouse strain RIIIS/J. Mvwf1 is a regulatory mutation in the gene encoding an N-acetylgalactosaminyltransferase, GALGT2, resulting in a tissue-specific switch in gene expression from intestinal epithelium to vascular endothelium. This ectopic expression results in aberrant post-translational modification of VWF, leading to accelerated clearance. The specific regulatory DNA sequences responsible for this remarkable transcriptional switch have not yet been identified.  To further characterize this regulatory mutation, we generated transgenic mice with overlapping C57BL/6J bacterial artificial chromosomes (BACs).  These experiments narrowed the genomic region sufficient for wild-type (C57BL6/J) intestine-specific Galgt2 expression to 83kb.  Direct sequence analysis of RIIIS/J identified a 35kb region of 2-3% divergence from C57BL6/J flanking Galgt2 exon 1.  To address the possibility of intergression, we studied strains ~2% divergent from Mus musculus.  Neither Mus spretus nor Mus spicilegus were similar to the Mvwf1 region.  PCR analysis of 49 strains identified nine strains, including four wild-derived strains, which share >55kb of the Mvwf1 haplotype block and the tissue-specific switch in Galgt2 expression.  Analysis of The Jackson Laboratory Mouse Phenome Database indicates that this haplotype and the corresponding Mvwf1 mutation account for five of the six highest aPTTs in the database.  This implies that reduced VWF:FVIII due to this unique Mvwf1 Galgt2 allele is the major cause of prolonged aPTTs in the mouse, and the prevalence of this allele suggests that it has been maintained through positive selective pressure.

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