Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia

In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in str iking contrast to its reported virtual absence in the black population in g eneral. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three scr eening methods resulted in the identification of seven different mutations in the coding region of the low density Lipoprotein (LDLR) gene in 10 of th e patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W R385Q, E38 7K, P678L, and R793Q) detected in single families. The Sotho patient with m issense 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 p osition -175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compar ed to controls and occurred in cis with mutation E387K in one family. Analy sis of four intragenic LDLR gene polymorphisms showed that the same chromos omal background was identified at this locus in the four FH patients with t he 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 separ ation approximately 3000 years ago.