Identification of two LDL receptor mutations causing familial hypercholesterolemia in Indian subjects

Familial hypercholesterolemia (FH) is a genetic disorder caused by numerous mutations in the low-density lipoprotein receptor (LDLR) gene. Mutational analyses of Indians in South Africa suggest the possibility of a high frequency of FH in India. This study aimed at identifying mutations in exons 3, 4, 9, and 14 of the LDLR gene among Indians and at eventually developing population-directed molecular-based screening assays. DNA samples from 25 hypercholesterolemic patients with clinical features of FH and 25 normal controls were analyzed for four known point mutations: W66G (exon 3), E207K (exon 4), E387K (exon 9), and P664L (exon 14), which are those most reported among Indian immigrants in South Africa. Subsequently, samples were screened for other mutations by modified heteroduplex analysis in these exons. Point mutations predicted to be common among Indians were absent in the samples analyzed. Heteroduplex analysis and sequencing revealed the presence of novel insertion mutations in two patients. Both mutations are single-nucleotide "G" insertions at position 242 in exon 3 and position 397 in exon 4. The observed mutations are predicted to cause a translational frameshift, encoding truncated LDLR proteins due to premature termination. The mutant proteins are likely to be degraded intracellularly and, therefore, are pathogenic.