Mutation-59c -> t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South Africanfamily with familial hypercholesterolaemia

The low-density lipoprotein receptor (LDLR) plays a major role in cholester ol homeostasis, Mutations in the regulatory region of the LDLR gene, althou gh rare, have been shown to alter transcriptional activity of the gene and can cause familial hypercholesterolaemia (FH). In this study, a transition (c-->t) was identified at nucleotide position -59 within repeat 2 of the LD LR promoter in a South African FH patient of mixed ancestry. By screening 1 7 family members of the index case for this promoter mutation, two addition al single base changes (-124c-->t and -175g-->t) were identified, located a t recently described cis-acting regulatory sequences of the LDLR promoter, Both the -59c-->t and the -124c-->t transitions were identified in the norm ocholesterolaemic son of the index patient. Reporter plasmids containing th e normal and mutant promoter fragments were constructed by directional clon ing. Transcription studies using a luciferase reporter system demonstrated that the -59c-->t mutation significantly reduces promoter activity in both the presence and absence of sterols (similar to 40% of normal activity), wh ile the -124c-->t variant increases transcription (similar to 160%) of the LDLR gene. The intra-familial phenotypic variability observed amongst indiv iduals with the -59c-->t mutation can probably be ascribed to allelic inter action, suggesting that: variation in the LDLR promoter region may contribu te significantly to the phenotypic expression of FH-related mutations in po pulations where these mutations prevail.