Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia

Graham, Colin A.; McClean, E.; Ward, Alana; Ec, Beattie; Martin, Sonya; O’Kane, Maurice; Young, Ian S.; Nicholls, D. P.

doi:10.1016/s0021-9150(99)00201-4

Cited by 56 publications

(44 citation statements)

References 24 publications

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“…Recently, Graham et al 7 have investigated genotype-phenotype correlations in heterozygous FH carrying different mutations of the LDL-R gene. They showed that frameshift (FS) mutations were associated with higher levels of LDL-C than those found in missense mutations.…”

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confidence: 99%

Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of the LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype

Bertolini¹,

Cantàfora²,

Averna³

et al. 2000

ATVB

133

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Abstract-Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (ϩ18%) and high density lipoprotein cholesterol lower (Ϫ5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients Ͼ30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptordefective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the ⑀2 allele and a raising effect of the ⑀4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol.Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors. (Arterioscler Thromb Vasc Biol. 2000;20:e41-e52.)

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confidence: 99%

Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of the LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype

Bertolini¹,

Cantàfora²,

Averna³

et al. 2000

ATVB

133

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“…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).…”

Section: Discussionmentioning

confidence: 68%

“…All these observations suggest that different mutations of the LDLR gene are associated with differences in plasma lipid levels, although the basis for these differences are not clear. One possible explanation could be that upregulation of the wild-type LDLR allele was affected by the nature of the mutant allele, or that some defective mutations had residual LDLR activities 13,14 On the other hand, genetic variability due to DNA polymorphisms of the wild type allele could quantitatively influence LDLc concentrations, as has been reported by Bétard et al 38 in French Canadian FH women carrying the French Canadian 10 kb deletion, which may further complicate the interpretation of data.…”

Section: Discussionmentioning

confidence: 98%

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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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“…2 The effects of these mutation classes on plasma lipoprotein levels and on risk of CVD have been studied extensively. [3][4][5][6][7][8] In these studies, however, patient populations were small and invariably selected through lipid clinics. Thus, other risk factors for CVD were likely to determine the excess mortality rates from FH, whereas the type of mutation had seemingly little or no relevant contribution.…”

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confidence: 99%

Low-Density Lipoprotein Receptor Gene Mutations and Cardiovascular Risk in a Large Genetic Cascade Screening Population

et al. 2002

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Background-A large cohort of patients with familial hypercholesterolemia (FH), free from selection for cardiovascular disease (CVD), and their unaffected relatives was collected by genetic cascade screening and examined for the influence of different mutations of the LDL receptor gene on lipoprotein levels and the risk of CVD. Multivariate analyses with adjustment for age, sex, and specific family ties were performed. Methods and Results-Significant variation of LDL levels was observed among 399 patients with FH with different mutations. Null alleles were associated with more severely elevated LDL cholesterol, whereas the frequent N543H/2393del9 mutation led to less elevated LDL cholesterol.

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Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia

Cited by 56 publications

References 24 publications

Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of the LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype

Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of the LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype

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

Low-Density Lipoprotein Receptor Gene Mutations and Cardiovascular Risk in a Large Genetic Cascade Screening Population

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