A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree

Timms, Kirsten M.; Wagner, Susanne; Samuels, Mark E.; Forbey, Kristian; Goldfine, Howard; Jammulapati, Srikanth; Skolnick, Mark H.; Hopkins, Paul N.; Hunt, Stephen; Shattuck, Donna

doi:10.1007/s00439-003-1071-9

Cited by 297 publications

(194 citation statements)

References 11 publications

(15 reference statements)

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“…We did not observe an association (inverse or otherwise) of del12 with other known risk factors for coronary artery disease, such as hypertension, smoking status, obesity, or type 2 diabetes (Table S8 in Several studies have shown a strong positive correlation between the effects of lipid-associated sequence variants on non-HDL cholesterol levels and the risk of coronary artery disease. [7][8][9][10]29 However, in our data, several published variants deviated from the overall trend (Fig. 3, and Table S9 in the Supplementary Appendix).…”

Section: Coronary Risk and Del12mentioning

confidence: 47%

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VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

et al. 2016

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BACKGROUNDSeveral sequence variants are known to have effects on serum levels of non-highdensity lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODSWe sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTSWe found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P = 1.0×10 −16 ), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P = 4.0×10 −6 ). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P = 1.8×10 −3 ). CONCLUSIONSASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)A BS TR AC T

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Section: Coronary Risk and Del12mentioning

confidence: 47%

“…[5][6][7][8][9][10] In our search for new variants that affect non-HDL cholesterol levels, we applied a method 11 of interrogating whole genomes in samples obtained from a large number of Icelanders. We then tested for association between implicated variants and the risk of coronary artery disease.…”

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confidence: 99%

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

et al. 2016

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“…This suggestion was confirmed by the finding that missense mutations in PCSK9 are associated with an autosomal dominant form of hypercholesterolemia (10)(11)(12). The clinical phenotype of these subjects is indistinguishable from two other autosomal dominant forms of hypercholesterolemia, both of which are caused by defective receptor-mediated clearance of LDL: (i) familial hypercholesterolemia, which is caused by mutations in the LDLR; and (ii) familial defective apolipoprotein B (apoB), caused by mutations in the ligand for the LDLR (13).…”

mentioning

confidence: 76%

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

Rashid

Curtis

Garuti

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

637

529

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PCSK9 encodes proprotein convertase subtilisin͞kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg͞dl in Pcsk9 ؊/؊ mice versus 96 mg͞dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9 ؊/؊ mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.low-density lipoprotein receptor ͉ lipoproteins ͉ proteinase ͉ sterol regulatory element-binding protein

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“…The third mutation, p.R218S, also in exon 4, was found in a French proband ascertained at age 45 with 402 mg/dl of total cholesterol and 293 mg/dl of LDL-C and presenting tendinous xanthoma and arcus corneae [Allard et al, 2005]. The p.D374Y mutation was reported in a hypercholesterolemic Utah kindred [Timms et al, 2004] and in three Norwegian families [Leren, 2004]. It was also found in three English families with 12 affected patients suffering from severe hypercholesterolemia, a family history of premature CHD, and requiring more stringent treatment than typical FH patients who are heterozygous for mutations in the LDL receptor gene [Sun et al, 2005].…”

Section: Biological Relevancementioning

confidence: 92%

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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A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree

Cited by 297 publications

References 11 publications

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

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

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