Genetic defects in postsqualene cholesterol biosynthesis

In humans and mice, four different genetic defects in the nine biosynthetic steps from lanosterol to cholesterol have been identified. They impair the activity of a putative C-3-sterol dehydrogenase (Nshdl, X-linked dominant bare patches/striated mutation in mice), the sterol Delta(8)-Delta(7) isome rase/EBP (Ebp, X-linked dominant tattered mutation in mice; chondrodysplasi a punctata (CDPX2) in humans), the Delta(24)-sterol reductase (autosomal re cessive desmosterolosis) and the Delta(7)-sterol reductase (DHCR7 gene, aut osomal recessive Smith-Lemli-Opitz syndrome in humans). These inborn errors in postsqualene cholesterol metabolism result in dysmorphogenetic syndrome s of variable severity. The X-linked dominant mutations result in mosaicism in females, as a result of X-inactivation, and midgestational lethality in males. The mechanisms by which the depletion of cholesterol or the accumul ation of intermediates impair morphogenetic programs are unclear. So far, n o cellular processes that require and intact cholesterol biosynthetic pathw ay have been identified, although the morphogenetic hedgehog-patched signal ing cascade is a candidate.