Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia
- Rochelle Thiarta,
- Charlotte L Scholtza,
- Joseph Vergotinea,
- Christiaan F Hoogendijka,
- J Nico P de Villiersa,
- Henrik Nissenb,
- Klaus Brusgaardb,
- Dairena Gaffneyc,
- Michael S Hoffsc,
- W J Hayward Vermaakd,
- Maritha J Kotzea
- aMRC Cape Heart Group, Division of Human Genetics, Faculty of Medicine, University of Stellenbosch, Tygerberg, South Africa, bDepartment of Clinical Chemistry, Odense University Hospital, Odense, Denmark, cDepartment of Pathological Biochemistry, Glasgow Royal Infirmary University NHS Trust, Glasgow, UK, dInstitute of Chemical Pathology, University of Pretoria, South Africa
- Dr Kotze, Division of Human Genetics, Faculty of Medicine, University of Stellenbosch, Francie van Zijl Drive, Clinical Building Room 2126, PO Box 19063, Tygerberg 7505, South Africa, mjk{at}gerga.sun.ac.za
- Revised 6 July 1999
- Accepted 15 February 2000
Abstract
In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in striking contrast to its reported virtual absence in the black population in general. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three screening methods resulted in the identification of seven different mutations in the coding region of the low density lipoprotein (LDLR) gene in 10 of the patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W, R385Q, E387K, P678L, and R793Q) detected in single families. The Sotho patient with missense mutation R232W was also heterozygous for a de novo splicing defect 313+1G→A. Several silent mutations/polymorphisms were detected in the LDLR and apolipoprotein B genes, including a base change (g→t) at nucleotide position −175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compared to controls and occurred in cis with mutation E387K in one family. Analysis of four intragenicLDLR gene polymorphisms showed that the same chromosomal background was identified at this locus in the four FH patients with the 6 bp deletion. Detection of the 6 bp deletion in Xhosa, Pedi, and Tswana FH patients suggests that it is an ancient mutation predating tribal separation approximately 3000 years ago.
