Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients

Slimani, Afef; Jelassi, Awatef; Jguirim, Imen; Najah, Mohamed; Rebhi, L.; Omezzine, Asma; Maatouk, Faouzi; Hamda, Khaldoun Ben; Kacem, Maha; Rabès, Jean-Pierre; Abifadel, Marianne; Boileau, Cathérine; Rouis, Mustapha; Slimane, Mohamed Naceur; Varret, Mathilde

doi:10.1016/j.atherosclerosis.2012.02.018

Cited by 22 publications

(15 citation statements)

References 32 publications

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“…Study indicates that this new PCSK9 variant is able to reduce the severity of FH, very probably acting as a loss-of-function variant. This finding should be confirmed by in vitro experiments [30].…”

Section: Molecular Defaults That Cause Adh In Tunisiamentioning

confidence: 51%

“…A recent study in Tunisia showed that 24% (9 out 38) of the ADH patients carrying an heterozygous mutation in the LDLR gene have a LDL-cholesterol level under the 60 th percentile of an age-and gender-matched reference population [30]. This discrepancy between the clinico/biological and molecular phenotype observed reveals the existence of factors that decrease the severity of the disease.…”

Section: Clinical and Biological Aspects Of Adh In Tunisia And Cascadmentioning

confidence: 99%

“…The mutation p.Ser493ArgfsX44 in exon 10 appears to be the most frequent mutation. [11,24,30,63,64].…”

Section: Molecular Defaults That Cause Adh In Tunisiamentioning

confidence: 99%

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Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

Jelassi¹,

Najah²,

Slimani³

et al. 2013

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Abstract:Autosomal dominant hypercholesterolemia (ADH) is characterized by an isolated elevation of plasmatic lowdensity lipoprotein (LDL), which predisposes to premature coronary artery disease (CAD) and early death. ADH is largely due to mutations in the low-density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), or the proprotein convertase subtilisin/kexin type 9 (PCSK9). Early diagnosis and initiation of treatment can modify the disease progression and its outcomes. Therefore, cascade screening protocol with a combination of plasmatic lipid measurements and DNA testing is used to identify relatives of index cases with a clinical diagnosis of ADH. In Tunisia, an attenuated phenotypic expression of ADH was previously reported, indicating that the establishment of a special screening protocol is necessary for this population.

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Section: Molecular Defaults That Cause Adh In Tunisiamentioning

confidence: 51%

Section: Clinical and Biological Aspects Of Adh In Tunisia And Cascadmentioning

confidence: 99%

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Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

Jelassi¹,

Najah²,

Slimani³

et al. 2013

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“…A recent study using the next-generation sequencing (NGS) to screen for a mutation in the three genes LDLR, APOB, and PCSK9 say that the NGS methodology could provide one rapid route to increasing the present low percentage of FH cases with a genetic diagnosis (Norsworthy et al, 2014). Regarding the seven patients who showed no mutations, the presence of the FH may probably be associated with other genes as APOB and PCSK9, as mutations in these two other genes cause patients presenting a similar phenotype to the ones with mutations in LDLR (Austin et al, 2004;Slimani et al, 2012).…”

Section: Resultsmentioning

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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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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“…In addition to genetic factors that contribute to hypercholesterolemia [26], excessive consumption of dietary SFA may also contribute to increased plasma cholesterol (total and LDL) levels [11]. A variety of nuts (almonds, walnuts, pistachios, peanuts, and macadamia nuts) have been reported to possess cholesterol-lowering benefits [5, 6, 8–10, 13–24, 27–34] suggesting that dietary modifications have the potential to improve lipid profiles and ultimately abate the prevalence of CVD.…”

Section: Discussionmentioning

confidence: 99%

Is Almond Consumption More Effective Than Reduced Dietary Saturated Fat at Decreasing Plasma Total Cholesterol and LDL-c Levels? A Theoretical Approach

Ortiz

Garcia

Kim

2012

Journal of Nutrition and Metabolism

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Hypercholesterolemia can be a consequence of excessive dietary saturated fatty acid (SFA), while almond-supplemented diets can improve lipid profiles. However, the differential and independent impacts of dietary SFA and almondsupplemented diets on plasma total cholesterol (pTC) and low-density lipoprotein (pLDL-c) concentrations have not been directly compared and are not well described. We reviewed the available data to construct multiple regression analyses to theoretically assess the impact of relative almond intake (RAI) and dietary SFA on reducing pTC and pLDL-c concentrations. Strong, negative correlations between RAI and percent change in mean pTC (R = 0.776; P = 0.005) and RAI and percent change in mean pLDL-c (R = 0.818; P = 0.002) were detected. The relationships between percent change in mean dietary SFA, and percent change in mean pTC and mean pLDL-c were weaker and only significant for pLDL-c. The multiple regression analyses demonstrated modest improvements in the strength of the correlations for both pTC (R = 0.804; P = 0.016) and pLDL-c (R = 0.855; P = 0.005). The models suggest that the increase in RAI contributes to the reduction in pTC and pLDL-c to a greater extent than a reduction in dietary SFA, but a simultaneous decrease in dietary SFA should further improve lipid profiles.

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Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients

Cited by 22 publications

References 32 publications

Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

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

Is Almond Consumption More Effective Than Reduced Dietary Saturated Fat at Decreasing Plasma Total Cholesterol and LDL-c Levels? A Theoretical Approach

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