Effect on plasma lipid levels of different classes of mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia.

Abstract

We used the single-strand conformational polymorphism method to screen 311 patients with familial hypercholesterolemia from London lipid clinics and Southampton and South West Hampshire health district for mutations in the 3' part of exon 4 of the low-density lipoprotein (LDL) receptor gene. This part of the gene codes for repeat 5 of the binding domain of the LDL receptor, which is known to be critical for the receptor-mediated removal of both triglyceride-rich lipoprotein remnants and LDL. Six previously described mutations were identified in 29 apparently unrelated individuals (9.3%), with the mutations all lying within a 50-bp fragment of the gene. Three of the mutations are null alleles producing no protein, and the other three lead to production of a defective protein. The effect of the different gene mutations on lipid levels was examined, after the data were combined with information on previously reported mutations in this patient group. Mean LDL cholesterol levels were highest in those F amilial hypercholesterolemia (FH) is caused by mutations in the low-density lipoprotein (LDL) receptor gene. 1 To date, it has been difficult to examine whether specific LDL receptor gene mutations show a different genotype-phenotype relation except in founder populations in which large numbers of earners for a particular mutation can be found. In such populations, recent studies have suggested that different mutations have different phenotypes such as lipid levels, expectation of clinical sequelae, and drug responsiveness. "5 However, because of their common origin, the patients may also share other genetic factors, and these comparisons may thus be confounded. Here, we report the first attempt to undertake such a study in a group of FH patients from a population with a complex spectrum of LDL receptor gene mutations by combining the characterized LDL receptor gene mutations into functional groups and examining the differences on baseline lipid levels among these groups.Five classes of mutations at the LDL receptor locus have been identified on the basis of the phenotypic O 1994 American Heart Association, Inc.individuals with a mutation creating a null allele (9.54 mmol/L) and were similar to levels in those individuals with a mutation affecting repeat 5 that resulted in the production of a defective protein (9.37 mmol/L). In this sample, previously identified patients with a defective protein mutation outside repeat 5 had lower mean levels of LDL cholesterol (7.78 mmol/L), which were similar to levels seen in patients in whom the specific mutation had not been identified (7.31 mmol/L). Overall, these differences were highly statistically significant (P<.001). These data reinforce the observations of other researchers that specific mutations in the LDL receptor gene are associated with different effects on plasma lipids and indicate that the phenotype is influenced by the genotype.

Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population

“…Our results and those of others 5,8,9,11,12,15,16 suggest that identification of mutations in the LDLR gene may allow a better assessment of clinical expression in these subjects with high CHD risk. In this sense, prospective studies should be performed to evaluate further the impact of genotype on severity of FH.…”

“…In contrast to this hypothesis, the results of previous studies 14,15,39,40 indicate that FH patients carrying null mutation not always have the highest TC and LDLc plasma values. In most studies, FH subject carriers of a mutation predicted to be severe (not only null mutations) or that affects five repeat of the binding domain region have the most atherogenic lipid profile (higher plasma values of TC and LDLc).…”

“…Similar results have been previously demonstrated. 14,15,40 One possible explanation is that FH patient carriers of null mutations (predicted to be severe) only express the normal receptor in the membrane of their cells. In contrast, FH patient carriers of the missense mutations express both the normal receptor and the altered receptors.…”

“…Carriers of S156L (n ¼ 5) were not included in this group because this mutation of exon 4 abolishes the binding of LDL, but not that of VLDL, causing only a mild reduction of the receptor function in vitro. 15 Missense mutations classified as no affecting the ligand binding repeat 3 -5 region were:…”

“…1 -4 FH shows great variability in phenotypic expression, which may be influenced by factors such as age, gender, diet, type of LDLR mutations or other genes. 5 -8 The type of LDLR gene mutation has been associated to different phenotype expression, 6,8,9 response to statins 10,11 and risk of premature CHD. 5 In Northern European FH populations, several studies have demonstrated that the type of mutation in the LDLR gene influences the FH phenotype expression.…”