International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Cunningham D
Columbus Children's Research Institute

Co-Authors: Swartzlander D, Caldas H, Armbruster D, Ray W, Herman G
Institutions: Columbus Children's Research Institute

Six human disorders of post-squalene cholesterol biosynthesis have been described. Common features include growth and mental retardation, major malformations, skeletal defects, and increasing severity with prenatal lethality for disorders involving earlier steps in the pathway. We are using microarray analysis of gene expression to unravel the pathogenesis of these disorders. Initial studies have focused on the X-linked bare patches (Bpa) mouse that results from mutations in a novel sterol dehydrogenase, Nsdhl, that functions in cholesterol biosynthesis. Heterozygous Bpa females have skin and skeletal abnormalities with a distribution reflecting random X-inactivation, while hemizygous males die as embryos between E8.5 and E9.5. To obtain a large, homogeneous population of Bpa cells, we generated doubly heterozygous females carrying a Bpa1H X chromosome and an X expressing a GFP transgene that undergoes random X-inactivation. Embryonic fibroblasts were cultured from mutant and wild type female embryos, and >99% pure populations of GFP-negative Bpa1H and wt cells were isolated by FACS. Labeled cDNA from parallel cultures of sorted Bpa or wt cells grown in normal or lipid-depleted media was hybridized to microarrays containing 22,000 mouse genes. In addition to increased expression of genes involved in cholesterol synthesis, mutant samples showed lower expression of cell cycle genes, higher expression of apoptosis inducing genes, and differential expression of several novel genes. Analysis of global gene expression patterns may reveal which of the many cellular and developmental processes that involve cholesterol and/or sterol intermediates are responsible for the pathogenesis in Bpa mice and in humans with cholesterol biosynthetic disorders.

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