Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (pcsk9) gain-of-function mutation

Mabuchi, Hiroshi; Noguchi, Teruhisa; Kobayashi, Junji; Kawashiri, M-a; Inoue, Tomio; Mori, Motoshichi; Tada, Hayato; Nakanishi, C.; Yagi, Kazuro; Yamagishi, Masayuki; Ueda, Kousei; Takegoshi, Tadayoshi; Miyamoto, Sayako; Inazu, Akihiro; Koizumi, Junichi

doi:10.1016/j.atherosclerosis.2014.05.263

Cited by 15 publications

(19 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients with loss-of-function PCSK9 mutations have lower plasma levels of LDL-C than the general population, and substantially lower cardiovascular risk, without any apparent adverse clinical phenotype [32]. Conversely, gain-of-function mutations of PCSK9 are the genetic basis of FH in some affected families [33,34]. Evolocumab is a fully human monoclonal IgG2 antibody selected for its ability to bind both wild-type and the D374Y [35] gain-of-function mutant PCSK9 [36].…”

Section: Introductionmentioning

confidence: 98%

Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology

Page

Watts

2015

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

The dramatic reduction in plasma levels of LDL-C attributable to evolocumab is anticipated to translate into lower rates of atherosclerotic cardiovascular disease, but this hypothesis remains to be proven. Also to be established are the long-term safety and economic benefits of evolocumab. PCSK9 inhibitors will also probably provide a valuable option for patients with statin intolerance, those with FH and patients with elevated plasma levels of Lp(a).

show abstract

Section: Introductionmentioning

confidence: 98%

Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology

Page

Watts

2015

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

show abstract

“…1 The frequency of mutations in LDLR in patients with familial hyper cholesterolaemia is ~70% in heterozygous individuals and 85% in homozygous indivi duals. 2 By contrast, mutations in APOB and PCSK9 have been detected in <5% of patients with familial hypercholesterolaemia in both Western and Asian countries. 2 True homozygotes have identical mutations in both alleles of the affected gene; however, most patients with familial hypercholesterolaemia are compound heterozygotes with different mutations in each LDLR allele.…”

mentioning

confidence: 94%

“…However, patients might effectively respond to treatment with statins and PCSK9 inhibitors if the homozygous familial hypercholesterolaemia is a result of a double mutation, such as a mutation in an LDLR allele paired with a gain-of-function mutation in PCSK9, or if the condition is a result of true homo zygous gain-of-function mutations in PCSK9. 2 Thus, in patients with suspected homo zygous disease, DNA analysis of the genes associated with familial hypercholesterol aemia in addition to measur ing residual LDLR activity is necessary for correct d iagnosis and effective t reatment (Figure 1d). …”

mentioning

confidence: 98%

“…2 By contrast, mutations in APOB and PCSK9 have been detected in <5% of patients with familial hypercholesterolaemia in both Western and Asian countries. 2 True homozygotes have identical mutations in both alleles of the affected gene; however, most patients with familial hypercholesterolaemia are compound heterozygotes with different mutations in each LDLR allele. Patients with double heterozygosity usually have a combination of a mutation in LDLR and a mutation in PCSK9, which results in a gain-of-function in the PCSK9 protein.…”

mentioning

confidence: 99%

“…Additional studies of the mechanism of action of PCSK9 might identify other potential targets for pharmacological inhibition of LDLR d egradation mediated by PCSK9. 2,3 Since 1981, statin treatments have been highly effective in patients with heterozygous familial hyperchosterolaemia. 5 On the basis of these findings, it was suggested that the goal of therapy in patients with familial hypercholesterolaemia should be to reduce plasma concentrations of LDL cholesterol without disrupting cholesterol delivery to cells.…”

mentioning

confidence: 99%

See 2 more Smart Citations

PCSK9 inhibitors for treating familial hypercholesterolaemia

Mabuchi

Nohara

2014

Nat Rev Endocrinol

View full text Add to dashboard Cite

Familial hypercholesterolaemia is caused by mutations in genes that code for proteins involved in cholesterol metabolism. Patients heterozygous for mutations in LDLR respond to statin treatment, whereas individuals with homozygous LDLR mutations do not. PCSK9 inhibitors have been developed for treating familial hypercholesterolaemia, and results are promising for patients with either heterozygous or homozygous familial hypercholesterolaemia.Familial hypercholesterolaemia is a common genetic disease characterized by elevated levels of cholesterol in the blood (as a result of increased plasma concentrations of LDL cholesterol), tendon xanthomas and premature coronary heart disease (CHD). Autosomal dominant familial hypercholesterolaemia can be caused by mutations in one or more genes involved in cholesterol metabolism, including LDLR (encodes the LDL receptor), PCSK9 (encodes proprotein convertase subtilisin/kexin type 9) and APOB (encodes the APOB protein, also known as apolipoprotein B). 1 The frequency of mutations in LDLR in patients with familial hyper cholesterolaemia is ~70% in heterozygous individuals and 85% in homozygous indivi duals. 2 By contrast, mutations in APOB and PCSK9 have been detected in <5% of patients with familial hypercholesterolaemia in both Western and Asian countries. 2 True homozygotes have identical mutations in both alleles of the affected gene; however, most patients with familial hypercholesterolaemia are compound heterozygotes with different mutations in each LDLR allele. Patients with double heterozygosity usually have a combination of a mutation in LDLR and a mutation in PCSK9, which results in a gain-of-function in the PCSK9 protein. 3 In the past decade, PCSK9 has emerged as a regulator of LDLR function that binds the extracellular domain of the protein, which results in activation of the destruction pathway and consequent degradation of LDLR. In mice, overexpression of PCSK9 reduces levels of LDLR and leads to hyper-LDL cholesterolaemia. Although most cases of familial hyper cholesterolaemia are caused by mutations that affect the structure and function of the LDLR protein, 1 mutations in genes that encode LDLR modulators, such as PCSK9, can result in increased or decreased LDLR function, which leads to hyper-LDL cholestero laemia, normocholesterolaemia or even hypo-LDL cholesterolaemia. 3 Two drugs (mipomersen, an antisense oligonucleotide that targets APOB mRNA, and lomitapide, a microsomal triglyceride transfer protein inhibitor) have been approved in the USA for the treatment of patients with homozygous familial hypercholesterolaemia. However, plasma levels of LDL cholesterol remain high in nearly all patients treated with these drugs, and additional therapy with extracorporeal adsorption using a dextran-sulphate-cellulose column (LDL-apheresis) is required. In one study, nonsense mutations in PCSK9 resulted in a 28% reduction in levels of LDL cholesterol and an 88% decrease in the risk of CHD. 4 These results, together with observations from studies in animal models, 3 pr...

show abstract

LDL‐cholesterol and PCSK9 in patients with familial hypercholesterolemia: influence of PCSK9 variants under lipid‐lowering therapy

Hamasaki

Sakane

Hara

et al. 2021

Clinical Laboratory Analysis

View full text Add to dashboard Cite

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease that exhibits high levels of circulating low-density lipoprotein (LDL) cholesterol (LDL-C) and an increased risk of coronary artery disease (CAD). 1 The most frequent causative gene, LDLR, encodes an LDL receptor (LDLR). 2 In addition, APOB is a causative gene that encodes for an apolipoprotein B component of LDL, which is a ligand of LDLR, but the frequency of variants is very low in Asian countries. 3,4 Furthermore, proprotein convertase subtilisin/kexin type 9 (PCSK9) is another major causative gene of FH, encoding the recently discovered PCSK9, although the frequency of PCSK9 variants is reported to be comparatively low. [3][4][5] PCSK9 promotes clathrin-mediated endocytosis of LDLR by forming a complex with

show abstract

Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (pcsk9) gain-of-function mutation

Cited by 15 publications

References 0 publications

Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology

Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology

PCSK9 inhibitors for treating familial hypercholesterolaemia

LDL‐cholesterol and PCSK9 in patients with familial hypercholesterolemia: influence of PCSK9 variants under lipid‐lowering therapy

Contact Info

Product

Resources

About