Comparative mapping of distal murine chromosome 11 and human 17q21.3 in a region containing a modifying locus for murine plasma von Willebrand factor level.
Type 1 von Willebrand disease (VWD) is a common inherited disorder characterized by mild to moderate bleeding and reduced levels of von Willebrand factor (VWF). An animal model for human type 1 VWD, the RIIIS/J mouse strain, exhibits a prolonged bleeding time and reduced plasma VWF levels. We have previously mapped the defect in RIIIS/J to distal mouse Chr 11, distinct from the Vwf locus on Chr 6. This locus, Mvwf, was localized to an approximately 0.5-cM interval, tightly linked to Gip, distal to Ngfr, and proximal to Hoxb. We have now used these genetic markers to construct a contig of yeast and bacterial artificial chromosomes and bacteriophage P1 clones spanning the approximately 300-kb Mvwf nonrecombinant interval. In a comparative mapping approach, mouse homologues of mapped human expressed sequence tags (ESTs) were localized relative to the candidate interval. Twenty-one sequence-tagged sites and ESTs from the corresponding human syntenic region 17q21.3 were ordered using the high-resolution Stanford TNG3 radiation hybrid panel. Based on the resulting radiation hybrid map and our mouse genetic and physical maps, the order of human and mouse genes in a >0.7-cM region appears to be conserved. Six genes localized to the Mvwf nonrecombinant interval by comparative mapping included orthologs of GNGT2, ATP6N1, and a nuclear domain protein. Seven other genes or ESTs were excluded from the candidate interval, including orthologs of PHB, PDK2, a speckle-type protein, and a UDP-galactose transporter. Using exon trapping, 10 additional putative expressed sequences were identified within the Mvwf nonrecombinant interval, including a previously cloned murine glycosyltransferase as well as exons showing sequence similarity to genes for Caenorhabditis elegans and Saccharomyces cerevisiae predicted proteins, an Arabidopsis thaliana ubiquitin-conjugating enzyme, and a Gallus gallus mRNA zipcode-binding protein. Further characterization of these putative genes could identify the dominant mutation responsible for low plasma VWF levels in RIIIS/J mice. These data may also aid in the localization of other disease loci mapped to this region, including the gene for tricho-dento-osseous syndrome and a murine locus for susceptibility to ozone-induced acute lung injury.
Mohlke
K L
KL
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA.
Purkayastha
A A
AA
Westrick
R J
RJ
Ginsburg
D
D
D000818:Animals; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D020224:Expressed Sequence Tags; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D016133:Polymerase Chain Reaction / Q000379:methods; D000091402:Prohibitins; D012313:RNA / Q000032:analysis; D015183:Restriction Mapping; D016324:Sequence Tagged Sites; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics*
D005819:Genetic Markers; C000717328:PHB protein, human; D000091402:Prohibitins; D014841:von Willebrand Factor; D012313:RNA