The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners

Kotze, Maritha J.; Langenhoven, E.; Warnich, Louise; Plessis, L. Du; Retief, A.E.

doi:10.1111/j.1469-1809.1991.tb00404.x

Cited by 80 publications

(42 citation statements)

References 6 publications

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“…In the light of the observations in this report, as well as those by other researchers, 25 it is now clear that different mutations are associated with differences in lipid levels, and it is likely that this will be associated with clinically different effects. It is also apparent that the phenotypic effect of the mutation is modulated by other genetic or environmental factors.…”

Section: Discussionmentioning

confidence: 72%

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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Section: Discussionmentioning

confidence: 72%

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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“…These 3 founder mutations together accounted for Ͼ80% of FH in Afrikaners and have been confirmed to cause defective LDL-R function at the cellular level. 17 Two subjects were homozygous for the FH-Gujerat mutation. 18 LDL-R mutations in the remaining 6 subjects are yet to be fully characterized, but these 6 patients fulfilled all the clinical criteria for homozygous FH.…”

Section: Resultsmentioning

confidence: 99%

“…15,16 DNA screening for 3 founder-related Afrikaner mutations, D206E (Afrik 1), V408 mol/L (Afrik 2), and D154N (Afrik 3), was performed in a single reaction by a multiplex amplification refractory mutation system-polymerase chain reaction, as previously described. 17 The DNA samples were also screened for mutation P664L (FH-Gujerat) previously identified in South African Indians. 18 After screening for familial defective apoB, subjects negative for these mutations underwent a more extensive search by heteroduplex and/or singlestrand conformational polymorphism analysis.…”

Section: Screening For Mutations In the Ldl-r Genementioning

confidence: 99%

Lipoprotein(a) in Homozygous Familial Hypercholesterolemia

Kraft

Lingenhel

Raal

et al. 2000

ATVB

122

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Abstract-Lipoprotein(a) [Lp(a)] is a quantitative genetic trait that in the general population is largely controlled by 1 major locus-the locus for the apolipoprotein(a) [apo(a)] gene. Sibpair studies in families including familial defective apolipoprotein B or familial hypercholesterolemia (FH) heterozygotes have demonstrated that, in addition, mutations in apolipoprotein B and in the LDL receptor (LDL-R) gene may affect Lp(a) plasma concentrations, but this issue is controversial. Here, we have further investigated the influence of mutations in the LDL-R gene on Lp(a) levels by inclusion of FH homozygotes. Sixty-nine members of 22 families with FH were analyzed for mutations in the LDL-R as well as for apo(a) genotypes, apo(a) isoforms, and Lp(a) plasma levels. Twenty-six individuals were found to be homozygous for FH, and 43 were heterozygous for FH. As in our previous analysis, FH heterozygotes had significantly higher Lp(a) than did non-FH individuals from the same population. FH homozygotes with 2 nonfunctional LDL-R alleles had almost 2-fold higher Lp(a) levels than did FH heterozygotes. This increase was not explained by differences in apo(a) allele frequencies. Phenotyping of apo(a) and quantitative analysis of isoforms in family members allowed the assignment of Lp(a) levels to both isoforms in apo(a) heterozygous individuals. Thus, Lp(a) levels associated with apo(a) alleles that were identical by descent could be compared. In the resulting 40 allele pairs, significantly higher Lp(a) levels were detected in association with apo(a) alleles from individuals with 2 defective LDL-R alleles compared with those with only 1 defective allele. This difference of Lp(a) levels between allele pairs was present across the whole size range of apo (a) ] plasma levels has been addressed in several studies in the past. 1-9 Because Lp(a) contains, in addition to apolipoprotein(a) [apo(a)], LDL (the principal ligand of the LDL-R), it was suggested that Lp(a) might be internalized and degraded via the LDL-R pathway. Consequently, it was postulated that Lp(a) concentrations should be increased in patients with familial hypercholesterolemia (FH), a condition caused by mutations in the LDL-R. 10 Several studies have focused on this theme, but conflicting results have been produced. One major reason for this dilemma might be the unique genetic control of Lp(a) levels.Unlike all other lipoproteins, Lp(a) levels show an extreme interindividual variability and are largely controlled by variation in 1 major gene, which is the structural gene for apo(a). 11,12 The apo(a) gene is highly polymorphic. One of the polymorphisms, the kringle IV (K-IV) polymorphism, which gives rise to the size polymorphism of the apo(a) protein, is responsible for a large part of the variation in Lp(a) plasma levels. In white populations, Ϸ50% of the variation in the Lp(a) concentration is explained by the number of K-IV repeats in the apo(a) allele. 11 The category of this effect is the same in every population studied to date, but the size of the ef...

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“…23 EDTA-blood was taken from 203 family members (103 FH patients, 57 relatives and 43 spouses) for analysis of their FH status. To determine Lp(a) concentrations and apo(a) genotype and phenotype samples were shipped on dry ice by air to Innsbruck.…”

Section: Subjectsmentioning

confidence: 99%

Concentrations of the atherogenic Lp(a) are elevated in familial hypercholesterolaemia: a sib pair and family analysis

et al. 1998

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The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners

Cited by 80 publications

References 6 publications

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

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

Lipoprotein(a) in Homozygous Familial Hypercholesterolemia

Concentrations of the atherogenic Lp(a) are elevated in familial hypercholesterolaemia: a sib pair and family analysis

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