A high incidence of mutations in exon 6 of the low-density lipoprotein receptor gene in Greek familial hypercholesterolemia patients, including a novel mutation

Familial hypercholesterolemia (FH) is an autosomal dominant disorder with a frequency of 1 in 500 in most western populations. It is characterized by hypercholesterolemia, which predisposes to the formation of tendon xanthomas and artherosclerotic plaques, increasing the risk of coronary artery disease (CAD) and premature death from myocardial infarction, often before the age of 55 years in FH heterozygotes and within the first two decades of life in the rare FH homozygotes (Goldstein and Brown, 1979). FH is usually caused by dysfunction of the low-density lipoprotein receptor (LDLR) protein, which in its mature form is a transmembranal protein of 839 amino acids. The LDLR gene is located on the distal short arm of chromosome 19, is 45 kb in length and has 18 exons (Yamamoto et al., 1984); to date more than 150 LDLR gene defects have been described in individuals with FH (Hobbs et al., 1992). They include large gene rearrangements (deletions or insertions), missense, nonsense and frame shift mutations. In most populations there is a general diversity of mutations, although in certain populations small numbers of mutations predominate due to a founder effect (Hobbs et al., 1992). In Greece, there have been substantial biochemical and epidemiological studies on FH, but so far the molecular basis has not been investigated. This report describes the initial results of a study to characterize the spectrum of LDLR mutations in Greece.