2 NOVEL POINT MUTATIONS CAUSING RECEPTOR-NEGATIVE FAMILIAL HYPERCHOLESTEROLEMIA IN A SOUTH-AFRICAN INDIAN HOMOZYGOTE

Two novel point mutations have been identified in the low density lipo protein receptor (LDLR) gene of a South African Indian patient with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). T he patient is a compound heterozygote, whose paternally-inherited alle le has a single base substitution of A to T at position +1. This conve rsion of the initiation codon ATG (methionine) to TTG (leucine) would abolish initiation of translation at the normal site, and consequently the synthesis of any normal LDLR molecules, The second mutation ident ified is a C to A base change al nucleotide position 1176 in exon 8, w hich creates a stop codon at cysteine-371. Except for previously-descr ibed polymorphisms in specific regions of the LDLR gene, the mutations identified in exons 1 and 8 were the only variants observed by screen ing enzymatically amplified genomic DNA comprising the entire coding a nd promoter region of the LDLR gene by combined heteroduplex-single-st rand conformation polymorphism analysis and by direct sequencing. Cult ured cells from the proband expressed no functional LDLR activity and contained no receptor protein that could be detected by antibody bindi ng. These findings are consistent with the nature of the two base chan ges identified and provide evidence that the mutations cause FH in the proband and his affected family members. The mutations, designated M- 21L and C371X, were absent in 17 apparently unrelated Indian hyperchol esterolemics and 200 normal chromosomes screened.