High frequency of the Lebanese allele of the LDLr gene among Brazilian patients with familial hypercholesterolaemia.

Figueiredo, Margarida Garcia de; Santos, Josiane; Alberto, Fernando; Zago, Marco Antônio

doi:10.1136/jmg.29.11.813

Cited by 16 publications

(13 citation statements)

References 7 publications

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“…The most frequent mutation causing FH among our cohort was the putative splicing mutation IVS7+10G>C (42%), followed by the mutations C681X (9%), D178Y (4%), and S326C (2%) ( Table 3). The articles of Figueiredo et al (1992) and Alberto et al (1999) are considered the first studies that reported the molecular characterization of FH caused by a deficiency of the LDLR gene in Brazil. These studies reported two mutations as the cause of FH in their patients: a 4-kb deletion involving exons 13 and 14 of the LDLR gene and the mutation C681X that creates a stop codon and the production of a truncated protein or a protein partially translated.…”

Section: Resultsmentioning

confidence: 99%

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Research Article Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil.

Molfetta

Zanette

Santos³

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Familial hypercholesterolemia (FH) is a dominant, autosomal disease characterized by high LDL levels in blood plasma, and is caused by a defect in the gene encoding the LDL receptor (LDLR). The clinical diagnosis is based on personal and familial history, physical examination findings, and measures of high LDL cholesterol concentrations. LDLR is a cell-surface glycoprotein that controls the level of blood plasma cholesterol and triglyceride by LDLR-mediated endocytosis. Here we sequenced the entire LDLR gene-coding region to screen for mutations in 32 patients diagnosed with FH, and we have found 20 mutations including synonymous, missense, and intronic mutations. Six of them were characterized as pathogenic mutations (D178Y, C184Y, S326C, C681X, IVS7+10G>C, and IVS11-10G>A). We have also found one intronic mutation not described so far (IVS11-63C>A). Our study corroborates the broad spectrum of mutations distributed along the entire LDLR gene, and we suggest that the genes APOB and PCSK9 should also be screened for mutations when considering the diagnosis of FH. It is already known that different types of mutations are directly associated with the phenotype heterogeneity presented by patients. Considering that Brazilian population is highly admixed, it is important to determine the geographic spectrum of LDLR mutations to provide information on the prognosis and treatment of each FH patient.

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Section: Resultsmentioning

confidence: 99%

“…The study of the molecular defects of the LDLR in Brazil was initiated by Figueiredo et al (1992) and Alberto et al (1999). These researchers identified the molecular basis of FH in 16 families.…”

Section: Introductionmentioning

confidence: 99%

Research Article Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil.

Molfetta

Zanette

Santos³

et al. 2017

Genet. Mol. Res.

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“…StuI and AvaII polymorphisms were analyzed by PCR amplification (see below) of a DNA The Brazilian population is composed of various ethnic groups, mainly Caucasians of European descent, Blacks, Amerindians, and, to a much lesser extent, Asians and Arabs (4). In a preliminary study we identified the Lebanese allele in 5 out of 10 unselected Brazilian families with FH, always in association with Arab ancestry, suggesting an important contribution of this ethnic group to the prevalence of FH in Brazil (5).…”

Section: Dna Analysismentioning

confidence: 90%

“…Ten patients were previously described in a preliminary search for the Lebanese mutation (5). Most of these patients are regularly followed at the University Hospital in Ribeirão Preto; blood samples from 6 families were generously provided by E. Quintão (School of Medicine, University of São Paulo, Brazil) and included patients from the States of Minas Gerais and Bahia.…”

Section: Patientsmentioning

confidence: 99%

“…The Lebanese allele was detected by the selective amplification of exon 14 of the LDLr gene followed by HinfI digestion, as previously described (5). To characterize the deletion identified in family 2, a segment containing the deletion breakpoints was amplified using the primers P1 (5'-CTTGGAGGA TGAAAAGGCTGG-3') and P2 (5'-TGACC TTTAGCCTGACGGTGGATG-3'), which are complementary to exons 12 and 15, respectively.…”

Section: Patientsmentioning

confidence: 99%

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The Lebanese mutation as an important cause of familial hypercholesterolemia in Brazil

Alberto

Figueiredo

Zago

et al. 1999

Braz J Med Biol Res

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Familial hypercholesterolemia (FH) is a common autosomal disorder that affects about one in 500 individuals in most Western populations and is caused by a defect in the low-density-lipoprotein receptor (LDLr) gene. In this report we determined the molecular basis of FH in 59 patients from 31 unrelated Brazilian families. All patients were screened for the Lebanese mutation, gross abnormalities of the LDLr gene, and the point mutation in the codon 3500 of the apolipoprotein B-100 gene. None of the 59 patients presented the apoB-3500 mutation, suggesting that familial defective ApoB-100 (FDB) is not a major cause of inherited hypercholesterolemia in Brazil. A novel 4-kb deletion in the LDLr gene, spanning from intron 12 to intron 14, was characterized in one family. Both 5' and 3' breakpoint regions were located within Alu repetitive sequences, which are probably involved in the crossing over that generated this rearrangement. The Lebanese mutation was detected in 9 of the 31 families, always associated with Arab ancestry. Two different LDLr gene haplotypes were demonstrated in association with the Lebanese mutation. Our results suggest the importance of the Lebanese mutation as a cause of FH in Brazil and by analogy the same feature may be expected in other countries with a large Arab population, such as North American and Western European countries. Correspondence

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The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

et al. 2009

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ABSTRACT:Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low-density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9). Familial hypercholesterolemia (FH) caused by mutation in the LDLR gene is the most frequent form of ADH. The incidence of FH is particularly high in the Lebanese population presumably as a result of a founder effect. In this study we characterize the spectrum of the mutations causing FH in Lebanon: we confirm the very high frequency of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH Lebanese probands recruited and identify other less frequent mutations in the LDLR. Finally, we show that the p.Leu21dup, an in frame insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9, known to be associated with lower LDL-cholesterol levels in general populations, is also associated with a reduction of LDL-cholesterol levels in FH patients sharing the p.C681X mutation in the LDLR. Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL-cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia.

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High frequency of the Lebanese allele of the LDLr gene among Brazilian patients with familial hypercholesterolaemia.

Abstract: We analysed the LDL receptor (LDLr) gene in 18 Brazilian patients with fami-

Cited by 16 publications

References 7 publications

Research Article Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil.

Research Article Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil.

The Lebanese mutation as an important cause of familial hypercholesterolemia in Brazil

The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

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