RECURRENT AND NOVEL LDL RECEPTOR GENE-MUTATIONS CAUSING HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA IN LA HABANA

The molecular basis of familial hypercholesterolemia (FH) in three fam ilies of Spanish descent from La Habana was investigated by the candid ate gene approach. The Arg3500Gln mutation of apolipoprotein B-100 was not found. Identification of low density lipoprotein receptor (LDLR) gene haplotypes segregating with FH guided the characterisation of thr ee point mutations by automated sequencing. One, a Val408 --> Met miss ense mutation, a founder mutation in Afrikaner FH patients, was recurr ent, being associated with a distinct DNA haplotype. The other two, Gl u256 --> Lys and Val776 --> Met missense mutations, were novel and mod ified highly conserved residues. These mutations were absent in normo- lipidemic subjects and were associated in heterozygous carriers with t wice the cholesterol levels observed in non-carriers. Noticeably, card iovascular complications were rarely observed in older heterozygotes, even in those with the Afrikaner FH-2 mutation. These findings confirm the molecular heterogeneity of LDLR gene mutations causing FH and the variability of their expression across different populations.