Journal Article

Mutation −59c→t in Repeat 2 of the LDL Receptor Promoter: Reduction in Transcriptional Activity and Possible Allelic Interaction in a South African Family with Familial Hypercholesterolaemia

Charlotte L. Scholtz, Armand V. Peeters, Christiaan F. Hoogendijk, Rochelle Thiart, J.N.P. de Villiers, Renate Hillermann, Jingwen Liu, A. David Marais and Maritha J. Kotze

in Human Molecular Genetics

Volume 8, issue 11, pages 2025-2030
Published in print October 1999 | ISSN: 0964-6906
Published online October 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.11.2025
Mutation −59c→t in Repeat 2 of the LDL Receptor Promoter: Reduction in Transcriptional Activity and Possible Allelic Interaction in a South African Family with Familial Hypercholesterolaemia

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The low-density lipoprotein receptor (LDLR) plays a major role in cholesterol homeostasis. Mutations in the regulatory region of the LDLR gene, although 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 LDLR promoter in a South African FH patient of mixed ancestry. By screening 17 family members of the index case for this promoter mutation, two additional single base changes (−124c→t and −175g→t) were identified, located at recently described cis-acting regulatory sequences of the LDLR promoter. Both the −59c→t and the −124c→t transitions were identified in the normocholesterolaemic son of the index patient. Reporter plasmids containing the normal and mutant promoter fragments were constructed by directional cloning. 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 (∼40% of normal activity), while the −124c→t variant increases transcription (∼160%) of the LDLR gene. The intra-familial phenotypic variability observed amongst individuals with the −59c→t mutation can probably be ascribed to allelic interaction, suggesting that variation in the LDLR promoter region may contribute significantly to the phenotypic expression of FH-related mutations in populations where these mutations prevail.

Journal Article.  4060 words.  Illustrated.

Subjects: Genetics and Genomics

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