Identification and properties of the proline664-leucine mutant LDL receptor in South Africans of Indian origin.

The incidence of familial hypercholesterolemia (FH) is high among South African Indians. The proline664-leucine low density lipoprotein (LDL)-receptor mutation was detected in four apparently unrelated Indian FH families in South Africa. This mutation was originally described in an FH subject (MM) of Indian (Gujerat province) origin (Soutar et al. 1989. Proc. Natl. Acad. Sci. 86: 4166-4170). All four South African families trace their origin to the vicinity of Surat in the Gujerat province of India. Haplotype analyses revealed that both LDL receptor genes in one of the homozygous patients are the same as those in the subject MM. The phenotype of the mutant protein was analyzed in skin fibroblasts of homozygous patients. [35S]methionine pulse-chase experiments revealed that the receptor precursors were slowly processed to mature receptors. Mature mutant receptors were degraded at faster than normal rates. This mutation, which is in the epidermal growth factor (EGF)-precursor-like domain of the LDL receptor, was previously reported to yield binding-defective receptors. Here we report that the affinity of the mutant LDL receptor for both LDL and beta-very low density lipoprotein (beta-VLDL) was normal and that the steady-state level of mutant receptors was about 20% of normal. Thus, the disease FH in these subjects is presumably due to the low steady-state level of receptor molecules that are functionally normal but exhibit accelerated turnover.