
<ArticleTitle>Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving <prot>sterolin-1</prot> and <prot>sterolin-2</prot>, encoded by <prot>ABCG5</prot> and <prot>ABCG8</prot>, respectively.</ArticleTitle>
<AbstractText>Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "<prot>sterolin-1</prot>" and encoded by <prot>ABCG5</prot>, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in <prot>sterolin-1</prot> could be identified. We identified another ABC transporter, located &#60;400 bp upstream of <prot>sterolin-1</prot>, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "<prot>sterolin-2</prot>" and encoded by <prot>ABCG8</prot>, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both <prot>sterolin-1</prot> and <prot>sterolin-2</prot> are indispensable for the regulation of sterol absorption and excretion. Identification of <prot>sterolin-1</prot> and <prot>sterolin-2</prot> as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.</AbstractText>
