DELETION OF EXON-15 OF THE LDL RECEPTOR GENE IS ASSOCIATED WITH A MILD FORM OF FAMILIAL HYPERCHOLESTEROLEMIA - FH-ESPOO

We describe a mutation of the low-density lipoprotein (LDL) receptor g ene, designated familial hypercholesterolemia (FH)-Espoo, which delete s exon 15 of the LDL receptor gene. The mutant receptor is predicted t o lack 57 amino acids, including 18 serine and threonine residues, whi ch are the sites of the clustered 0-linked sugars of the receptor. Stu dies on 10 carriers of this gene revealed that FH-Espoo is associated with an exceptionally mild form of FH. Thus, in conditions in which ce ll proliferation was rendered dependent on the function of LDL recepto rs, lymphocytes from the patients with the FH-Espoo allele had a growt h rate intermediate between those from healthy subjects and patients w ith the FH-Helsinki gene, a mutation known to abolish LDL receptor fun ction. The in vivo fractional catabolic rate of LDL apolipoprotein B w as lower than normal in the two FH-Espoo heterozygotes studied. Althou gh higher than those in healthy controls, the serum LDL cholesterol co ncentrations in patients with the FH-Espoo gene were significantly low er than those in patients with the FH-Helsinki mutation. The thickness of the Achilles tendons was within the normal limits in subjects with the FH-Espoo gene. Our study suggests that moderate varieties of hype rcholesterolemia, ie, those not considered to represent FH, may occasi onally be due to subtle LDL receptor gene mutations.