Two novel point mutations have been identified in the low density lipoprotein receptor (LDLR) gene of a South African Indian patient with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The patient is a compound heterozygote, whose paternally-inherited allele has a single base substitution of A to T at position + 1. This conversion 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 identified is a C to A base change at nucleotide position 1176 in exon 8, which creates a stop codon at cysteine-371. Except for previously-described polymorphisms in specific regions of the LDLR gene, the mutations identified in exons 1 and 8 were the only variants observed by screening enzymatically amplified genomic DNA comprising the entire coding and promoter region of the LDLR gene by combined heteroduplex-single-strand conformation polymorphism analysis and by direct sequencing. Cultured cells from the proband expressed no functional LDLR activity and contained no receptor protein that could be detected by antibody binding. These findings are consistent with the nature of the two base changes 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 hypercholesterolemics and 200 normal chromosomes screened.