International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Dr. Gail Herman
Children's Research Institute
700 Children's Dr.  Rm W403
Columbus,OH 43205

Co-Authors:  Wang J, Peters J, Cattanach B, Kelley RI
Institutions: Children's Research Institute, Mammalian Genetics Unit and Mouse Genome Centre,  Kennedy Krieger Institute

The X-linked dominant male-lethal mouse mutation bare patches (Bpa) results from mutations in Nsdhl. The Nsdhl enzyme is involved in the removal of C-4 methyl groups in the cholesterol biosynthetic pathway. Male embryos for several Bpa alleles die during midgestation (day 10.5-13.5 pc). Since cholesterol levels in affected male embryos at the time of death are normal, the pathogenesis of the male lethality must be caused by another mechanism. Placentas from affected male embryos are smaller than those of normal littermates (p < 0.001), and the labyrinthine layer of the placenta appears thinner, disorganized, and has fewer fetal vessels by PECAM staining. There are also statistically significant differences in placental thickness between affected male and affected female placentas. Since most cells in the female rodent placenta undergo preferential inactivation of the paternal X Chr, we believe that cells derived from allantoic mesoderm that undergo random X-inactivation are responsible for or contribute to the male lethality. Finally, we have been unsuccessful in attempts to generate transgenic mice that overexpress Nsdhl. Preliminary data from experiments in which a tyrosinase minigene was coinjected with an Nsdhl cDNA suggest that such overexpression may be lethal during embryogenesis. A possible explanation could include feedback regulation of isoprenoid synthesis earlier in the cholesterol biosynthetic pathway.

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