Abstract

Human cells maintain their cholesterol homeostasis by regulated cleavage of membrane bound transcription factors, so-called sterol regulatory element binding proteins (SREBPs). If cells are deprived of cholesterol, SREBPs are cleaved by two proteolytic steps. The NH₂-terminal domain of the SREBPs is released from the membranes of the endoplasmic reticulum and transported into the nucleus, where it binds to specific nucleotide sequences in the promoters of the low density lipoprotein receptor gene and of key genes involved in cholesterol and triglyceride homeostasis. Given the central role of SREBPs in the regulation of cholesterol metabolism, we investigated whether subjects with inherited forms of high plasma cholesterol carry specific sequence variations in SREBP-2 that might be involved in the development of hypercholesterolaemia. Exons 5 to 10, encoding the DNA binding and the regulatory domains of SREBP-2, were screened for sequence variations in a cohort of 70 hypercholesterolaemic subjects. Two missense mutations (V623M, R645Q) in the regulatory domain, one single nucleotide polymorphism (R371K) in the DNA binding domain, and one translationally silent mutation (P433P) were identified in SREBP-2. However, none of the mutations found in the regulatory domain could be detected in 167 subjects of a random control sample. A potential causative mechanism of these mutations for high plasma cholesterol concentrations is discussed. In summary, this is the first report of mutations in the human SREBP-2 gene to suggest that these and/or other mutations in this key regulator of cholesterol metabolism are associated with hypercholesterolaemia.