Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia

Pisciotta, Livia; Oliva, Claudio Priore; Cefalù, Angelo Baldassare; Noto, Davide; Bellocchio, Antonella; Fresa, Raffaele; Cantàfora, Alfredo; Patel, Dilip D.; Averna, Maurizio; Tarugi, Patrizia; Calandra, Sebastiano

doi:10.1016/j.atherosclerosis.2005.08.015

Cited by 100 publications

(56 citation statements)

References 27 publications

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“…Additive effects of mutations in the LDLR and PCSK9 genes on the phenotype of FH have been reported in several studies [Allard et al, 2005;Pisciotta et al, 2006]. Combined mutations in LDLR and PCSK9 are associated with a severe phenotype similar to homozygous FH.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 92%

“…The proband's mother, who carried only the p.R496W mutation in PCSK9, had a typical FH phenotype and carotid atherosclerosis with 40 to 60% stenosis. The second proband had a similar severe phenotype and carried a nonsense mutation of the LDLR gene (p.Y419X) and an amino acid substitution in PCSK9 protein (p.N425S) [Pisciotta et al, 2006]. This PCSK9 variant is very rare in Caucasians but more frequent in Blacks and might be carried by either low-or high-LDL subjects [Kotowski et al, 2006].…”

Section: Genotype-phenotype Correlationmentioning

confidence: 97%

“…The p.R469W variant is rare and was found only in high-LDL subjects in the Dallas heart study [Kotowski et al, 2006]. Pisciotta et al [2006] reported a first proband with a clinical diagnosis of homozygous FH that was heterozygous for the p.E228 K mutation in the LDLR and carried the p.R496W mutation in PCSK9. The proband's mother, who carried only the p.R496W mutation in PCSK9, had a typical FH phenotype and carotid atherosclerosis with 40 to 60% stenosis.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

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Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

et al. 2009

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Hypercholesterolemia is one of the major causes of coronary heart disease (CHD). The genes encoding the low-density lipoprotein receptor and its ligand apolipoprotein B, have been the two genes classically implicated in autosomal dominant hypercholesterolemia (ADH). Our discovery in 2003 of the first mutations of the proprotein convertase subtilisin kexin 9 gene (PCSK9) causing ADH shed light on an unknown actor in cholesterol metabolism that since then has been extensively investigated. Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD. In this review, we focus on reported variants, and their biological, clinical, and functional relevance. We also highlight the spectrum of hypercholesterolemia or hypobetalipoproteinemia phenotypes that are already associated with mutations in PCSK9. Finally, we present future prospects concerning this therapeutic target that might constitute a new approach to reduce cholesterol levels and CHD, and enhance the effectiveness of other lipid-lowering drugs.

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Section: Genotype-phenotype Correlationmentioning

confidence: 92%

Section: Genotype-phenotype Correlationmentioning

confidence: 97%

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

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Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

et al. 2009

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“…The sequence of APOB, PCSK9, and LDL-r genes was performed as previously described. 5,24 The sequence of PCSK9 gene was performed in all APOB"negative" FHBL patients (18 subjects) and in all hypocholesterolemic blood donors (102 subjects). PCSK9 variants found by systematic sequencing of PCSK9 gene in these subjects were screened in the other population samples by direct sequencing of the appropriate amplicons.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

Fasano

Cefalù

Leo

et al. 2007

ATVB

Self Cite

124

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Objectives-The PCSK9 gene, encoding a pro-protein convertase involved in posttranslational degradation of low-density lipoprotein receptor, has emerged as a key regulator of plasma low-density lipoprotein cholesterol. In AfricanAmericans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. The aim of this study was to assess whether loss of function mutations of PCSK9 were a cause of familial hypobetalipoproteinemia and a determinant of low-plasma low-density lipoprotein cholesterol in whites. Methods and Results-We sequenced PCSK9 gene in 18 familial hypobetalipoproteinemia subjects and in 102 hypocholesterolemic blood donors who were negative for APOB gene mutations known to cause familial hypobetalipoproteinemia. The PCSK9 gene variants found in these 2 groups were screened in 42 subjects in the lowest (Ͻ5 th ) percentile, 44 in the highest (Ͼ95 th ) percentile, and 100 with the average plasma cholesterol derived from general population. In one familial hypobetalipoproteinemia kindred and in 2 hypocholesterolemic blood donors we found a novel PCSK9 mutation in exon 1 (c.202delG) resulting in a truncated peptide (Ala68fsLeu82X). Two familial hypobetalipoproteinemia subjects and 4 hypocholesterolemic blood donors were carriers of the R46L substitution previously reported to be associated with reduced low-density lipoprotein cholesterol as well as other rare amino acid changes (T77I, V114A, A522T and P616L) not found in the other groups examined. Conclusions-We discovered a novel inactivating mutation as well as some rare nonconservative amino acid substitutions of PCSK9 in white hypocholesterolemic individuals.

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“…20 In addition, PCSK9 mutation has been linked to accelerated ApoB production, 21 and can worsen the phenotype of heterozygous FH. 22 One of the PCSK9 variants we found in this patient was previously, though not definitively, linked to alterations in cholesterol levels; it was initially associated with elevated cholesterol, but a subsequent, larger study in African Americans linked it with both unusually high and unusually low LDL cholesterol values. 11 It is possible that the effect of PCSK9 alteration varies by context: the previously reported mutant may not sufficiently alter cholesterol regulation to cause a noticeable phenotype in isolation, but is capable of worsening dyslipidemia when combined with defective LDLR.…”

Section: Discussionmentioning

confidence: 70%

LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

et al. 2008

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Familial hypercholesterolemia (FH) is the most common form of autosomal-dominant hypercholesterolemia, and is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Heterozygous FH is characterized by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular disease, whereas homozygous FH results in more severe LDL cholesterol elevation with death by 20 years of age. We present here the case of an African-American female FH patient presenting with a myocardial infarction at the age of 48, recurrent angina pectoris and numerous coronary artery stents. Her pretreated LDL cholesterol levels were more typical of a homozygous FH pattern and she was resistant to conventional lipid-lowering treatment, yet her other clinical parameters were not necessarily consistent with homozygous FH. Genetic testing revealed two LDLR variants on the same chromosome: one a novel missense mutation in exon 14 (Cys681Gly) and the other a promoter variant (IVS1-217C4T) previously shown to result in increased LDLR transcription. Disease-associated PCSK9 or APOB mutations were not identified in this individual. Overall, her genetic and clinical profile suggests that enhanced expression of the mutant LDLR allele resulted in a severe phenotype with characteristics of both heterozygous and homozygous FH.

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Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia

Cited by 100 publications

References 27 publications

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

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