Inheritance of two different alleles of the low-density lipoprotein (LDL)-receptor gene carrying the recurrent Pro664Leu mutation in a patient with homozygous familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is caused by mutations in the low-density lipoprotein (LDL)-receptor gene that result in impaired clearance of plasma LDL and increased risk of coronary heart disease. Numerous different mutations have been found in FH patients worldwide, the majority of which are infrequent in out-bred populations and account for 2% or less of patients with the disorder in large cohorts. Thus, it was surprising to find that two homozygous FH patients referred to a single hospital in the UK were both apparently homozygous for the Pro664Leu mutation. One, an Asian patient, was a true homozygote. The other, of English origin, had inherited two different alleles of the LDL-receptor gene with the same mutation from unrelated parents, as inferred from the haplotype of polymorphic markers. A third, clinically homozygous FH patient, despite being the offspring of first cousins, had inherited one 'Asian' Pro664Leu allele, but an allele with a l-bp deletion in exon 5 from the other parent. The Pro664Leu mutation in the LDL-receptor gene has now been described in heterozygous patients of very different ethnic origin and is associated with different haplotypes, suggesting that the same base change at a CpG may have recurred as many as six times.