Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations.

Kotze, Maritha J.; Villiers, Willem J. de; Steyn, Krisela; Kriek, J A; Marais, A. David; Langenhoven, E.; Herbert, J.S.; Roggen, J. Frans Graadt van; Westhuyzen, Deneys R. van der; Coetzee, Gerhard A.

doi:10.1161/01.atv.13.10.1460

Cited by 104 publications

(55 citation statements)

References 28 publications

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“…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.…”

Section: Discussionsupporting

confidence: 71%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2003

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Few data are available on genotype -phenotype interactions among familial hypercholesterolemia (FH) patients in South European populations and there are no data about the influence of R3500Q mutation on lipoprotein phenotype compared to low-density lipoprotein receptor (LDLR) mutations. The objective of the study is to analyze the influence of mutations in the LDLR and apolipoprotein B (apoB) genes on lipoprotein phenotype among subjects clinically diagnosed of FH living in East Spain. In all, 113 FH index patients and 100 affected relatives were studied. Genetic diagnosis was carried out following a protocol based on Southern blot and PCR-SSCP analysis. A total of 118 FH subjects could be classified into three groups according to the type of LDLR mutations (null mutations, missense mutations affecting the ligand binding 3-5 repeat, and missense mutations outside this domain). In addition, the lipoprotein phenotype of these FH groups was compared with 19 heterozygous subjects with familial ligand-defective apoB (FDB), due to R3500Q mutation. FH patients carrying missense mutations affecting the ligand binding repeat 3-5 showed total and LDL cholesterol levels significantly higher than FH patients with missense mutations in other LDLR domains or FDB patients. FH subjects carrying null mutations showed lower high-density lipoprotein cholesterol plasma values compared to FH carrying missense mutations. FDB subjects showed the lowest total and LDL cholesterol plasma values. In conclusion, the type of LDLR gene mutation and R3500Q mutation influences the lipoprotein phenotype of FH population from East Spain.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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“…3336 In a large study of FH patients, 33 men with CAD had significantly higher LDL cholesterol than those free of disease (7.13 versus 6.51 mmol/L), and in a recent study from South Africa, 4 FH patients with CAD had 8% higher cholesterol than those without CAD. A significant positive correlation between intimamedia thickening in the femoral artery and total serum cholesterol levels in FH patients has been reported.…”

Section: Discussionmentioning

confidence: 97%

“…The explanation for this observation is unclear but is in agreement with results from other researchers. 4 The increase in plasma cholesterol levels is approximately 0.8 mmol/L per decade in the group with the defective protein compared with approximately 0.5 mmol/L per decade in the general British population. 28 -29 In the general population a clear relation exists between the magnitude of hypercholesterolemia and the prevalence and incidence of coronary artery disease (CAD) 30 ' 31 as well as the onset of symptoms, with an increase of 1.3 mmol/L in plasma cholesterol associated with a CAD onset 10 years earlier.…”

Section: Discussionmentioning

confidence: 97%

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

Gudnason

Day

Humphries

1994

Arterioscler Thromb

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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.

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“…The homozygous form of FH is much more severe and depending on the type of mutation may cause death in the early decades of life [1,2]. Several different factors may affect the manifestation of FH such as age, gender, diet, type of LDLR mutations and other gene mutations [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterization of Iranian Patients with Possible Familial Hypercholesterolemia

et al. 2011

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Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism caused mainly by mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B 100 (APOB) genes. Until now, the molecular basis of FH has been demonstrated in detail in many populations, but there is still very limited Molecular data concerning FH in Iran. The aim of this study was to characterize the LDLR and APOB gene mutations in an Iranian population. A total of 30 non-related Iranian possible FH subjects were studied. Diagnosis of FH was based on the Dutch Lipid Clinic Network diagnostic criteria. All samples were initially tested for three common APOB gene mutations including R3500Q, R3500 W and R3531C using PCR-RFLP assay. Subsequently, promoter and coding region of the LDLR gene was screened by PCR-SSCP analysis and positive results were confirmed by DNA sequencing. Four previously reported polymorphisms 1413G [ A, 1725C [ T, 1773T [ C and 2140 ? 5G [ A were found in *17% (5/30) of population studied.Moreover, no variation was found in APOB gene. Our data indicated that LDLR and APOB gene mutations have not contribution to possible FH in Iranian population studied here. However, we examined three common APOB mutations and LDLR in only 30 patients, and to determine the role of these genes in developing FH in Iran, more FH samples and populations needed to be investigated for the mutations of the related genes.

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Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations.

Cited by 104 publications

References 28 publications

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

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

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

Molecular Characterization of Iranian Patients with Possible Familial Hypercholesterolemia

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