Genetic disorders of cholesterol biosynthesis in mice and humans

Over the past few years, the number of identified inborn errors of choleste rol biosynthesis has increased significantly. The first inborn error of cho lesterol biosynthesis to be characterized, in the mid 1980s, was mevalonic aciduria. In 1993, Irons et al. (1) (M. Irons, E. R. Elias, G. Salen, G. S. Tint, and A. K. Batta, Lancet 341:1414, 1993) reported that Smith-Lemli-Op itz syndrome, a classic autosomal recessive malformation syndrome, was due to an inborn error of cholesterol biosynthesis. This was the first inborn e rror of postsqualene cholesterol biosynthesis to be identified, and subsequ ently additional inborn errors of postsqualene cholesterol biosynthesis hav e been characterized to various extent. To date, eight inborn errors of cho lesterol metabolism have been described in human patients or in mutant mice . The enzymatic steps impaired in these inborn errors of metabolism include mevolonate kinase (mevalonic aciduria as well as hyperimmunoglobulinemia D and periodic fever syndrome), squalene synthase (Ss-/- mouse), 3 beta -hyd roxysteroid Delta (14)-reductase (hydrops-ectopic calcification-moth-eaten skeletal dysplasia), 3 beta -hydroxysteroid dehydrogenase (CHILD syndrome, bare patches mouse, and striated mouse), 3 beta -hydroxysteroid Delta (8),D elta (7)-isomerase (X-linked dominant chondrodysplasia punctata type 2, CHI LD syndrome, and tattered mouse), 3 beta -hydroxysteroid Delta (24)-reducta se (desmosterolosis) and 3 beta -hydroxysteroid Delta (7)-reductase (RSH/Sm ith-Lemli-Opitz syndrome and Dher7-/-mouse). Identification of the genetic and biochemical defects which give rise to these syndromes has provided the first step in understanding the pathophysiological processes which underli e these malformation syndromes. (C) 2001 Academic Press.