Human Molecular Genetics, 2003, Vol. 12, Review Issue 1 R75-R88
DOI: 10.1093/hmg/ddg072
© 2003 Oxford University Press
Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes
Center for Molecular and Human Genetics, Columbus Children's Research Institute and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
Received January 16, 2003; Accepted January 22, 2003
Since 1998, five disorders involving enzyme defects in post-squalene cholesterol biosynthesis have been identified—desmosterolosis, X-linked dominant chondrodysplasia punctata, CHILD syndrome, lathosterolosis, and hydrops-ectopic calcification-moth-eaten skeletal dysplasia. They join the most common cholesterol biosynthetic disorder, Smith–Lemli–Opitz syndrome, whose underlying defect was identified in 1993. All are associated with major developmental malformations that are unusual for metabolic disorders. The existence of mouse models for five of these disorders is beginning to enable more detailed developmental and in vitro studies examining the mechanisms involved in disease pathogenesis. In this review, an overview of the cholesterol biosynthetic pathway will be presented. Clinical features of the human disorders and mouse models of post-squalene cholesterol biosynthesis will then be discussed.
* To whom correspondence should be addressed at: Columbus Children's Research Institute, 700 Children's Dr. Rm W403, Columbus, OH 43205, USA. Tel: 614-722-2848; Fax: 614-722-2817; Email: hermang{at}pediatrics.ohio-state.edu
A special issue of Biochimica Biophysica Acta entitled ‘Cholesterol in the year 2000’, volume 1529, 2000, is dedicated to Konrad Bloch and contains excellent reviews detailing some of the research on cholesterol metabolism since Bloch's initial discoveries.
Although there are approximately 30 enzymatic reactions in the cholesterol biosynthetic pathway, there are fewer distinct enzymes because more than one reaction may be catalyzed by a single enzyme (i.e. sterol C-4 methyl oxidase) and the C-4 demethylase complex of three enzymes is involved in sequential removal of both C-4 methyl groups.
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