Low density lipoprotein receptor mutations in South African homozygous familial hypercholesterolemic patients

The binding and catabolism of low density lipoprotein (LDL) were studied in cultured skin fibroblasts and/or Epstein-Barr virus-transformed lymphoblastoid cells from 20 familial hypercholesterolemic (FH) homozygotes of 14 Afrikaner kindreds. Cells from available heterozygotes were also analyzed. Good resolution between the normal, heterozygote, and homozygote groups was obtained on the basis of these assays using either cell type. Results obtained with fibroblasts allowed the classification of 13 of these kindreds as being typically receptor-defective, and one kindred with two homozygotes as being receptor-negative. Fibroblasts from homozygotes of the receptor-defective class expressed LDL receptor activities which varied between 3% and 25% of normal. Where two homozygotes from the same family were available for assays (six families), both yielded similar activities. In contrast to fibroblasts, all the lymphoblastoid cells derived from FH homozygotes yielded LDL receptor activities equal to or less than 10% of normal; in a number of cases no significant 125I-LDL binding was detectable. The use of lymphoblastoid cells provides a convenient means for screening for FH at the cellular level. Our results indicate a predominance of a receptor-defective type of abnormality, which is consistent with a founder gene effect in the Afrikaner population.