Deletion of exon 15 of the LDL receptor gene is associated with a mild form of familial hypercholesterolemia. FH-Espoo.

Abstract

We describe a mutation of the low-density lipoprotein (LDL) receptor gene, designated familial hypercholesterolemia (FH)-Espoo, which deletes exon 15 of the LDL receptor gene. The mutant receptor is predicted to lack 57 amino acids, including 18 serine and threonine residues, which are the sites of the clustered 0-linked sugars of the receptor. Studies on 10 carriers of this gene revealed that FH-Espoo is associated with an exceptionally mild form of FH. Thus, in conditions in which cell proliferation was rendered dependent on the function of LDL receptors, lymphocytes from the patients with the FH-Espoo allele had a growth rate intermediate between those from healthy subjects and patients with the FH-Helsinki gene, a mutation known to abolish LDL receptor function. The in vivo fractional catabolic rate of LDL apolipoprotein B was lower than normal in the two FH-Espoo heterozygotes studied. Although higher than those in healthy controls, the serum LDL cholesterol concentrations in patients with the FH-Espoo gene were significantly lower 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 hypercholesterolemia, ie, those not considered to represent FH, may occasionally be due to subtle LDL receptor gene mutations. (Arterioscler Thromb. 1993;13:1680-1688 KEY WORDS • apolipoprotein B • apolipoprotein E • cholesterol • DNA • Finland • LDL receptor gene • familial hypercholesterolemia

The Agenda for Familial Hypercholesterolemia

“…[40][41][42] The functional defects in the LDL receptor are complex, and a mutation can belong to >1 class. 37 In practice, it is simpler to classify mutations into 2 groups: LDL receptor-deficient mutations (ie, null alleles that do not produce LDL receptor protein) and LDL receptor-defective mutations (ie, gene variants that affect function such as the interaction with the ligand-binding domain of LDL).…”

“…Numerous studies have investigated the relationship between specific mutations or mutation classes and the clinical expression of the disease. 40,[53][54][55][56][57][58][59] The major effect of the type of LDL receptor mutation relates to the contribution of the defect to the LDL-C level. 59 Additional genetic variants that affect LDL-C level to a small degree explain variation in LDL-C levels independently of the major FH-causing gene.…”

Chicken Oocytes and Somatic Cells Express Different Splice Variants of a Multifunctional Receptor

“…Rather, it appears that regulation of surface expression of the variants in different cells or tissues holds the key to ligand targeting (Schneider, 1995). In strong support of this notion, deletion of the O-linked sugar domain in LR7, which is associated with very poor surface expression, brings about the clinical symptoms of familial hypercholesterolemia (Kajinami et al, 1988;Koivisto et al, 1992Koivisto et al, , 1993) despite unaltered ligand recognition by the mutant protein in vitro (Davis et al, 1986). We postulate that the chicken's female germ cell has specific means to express high levels of LR8Ϫ on the cell surface (George et al, 1987;Barber et al, 1991), and that this might be a regulatory mechanism for initiating oocyte growth.…”

Breast Carcinoma Epithelial Cells Express a Very Low‐Density Lipoprotein Receptor Variant Lacking the O‐Linked Glycosylation Domain Encoded by Exon 16, But with Full Binding Activity for Serine Proteinase/Serpin Complexes and Mr‐40000 Receptor‐Associated Protein

“…These findings are analogous to findings with LDLR, where lack of the O-linked glycosylation domain does not lead to detectable changes in ligand binding and endocytosis capacity (Davis et al, 1986). Nevertheless, humans lacking the exon encoding the O-linked glycosylation domain have a mild hypercholesterolemia (Kajinami et al, 1988;Koivisto et al, 1993), showing an important function for that domain in vivo. This may also be the case for VLDLR.…”