Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

  title={Mutations in PCSK9 cause autosomal dominant hypercholesterolemia},
  author={Marianne Abifadel and Mathilde Varret and Jean-Pierre Rab{\`e}s and Delphine Allard and Khadija Ouguerram and Martine Devillers and Corinne Cruaud and Suzanne Benjannet and Louise Wickham and Dani{\`e}le Erlich and Aur{\'e}lie Derr{\'e} and Ludovic Vill{\'e}ger and Michel Farnier and Isabel Beucler and Eric Bruckert and Jean Chambaz and Bernard Chanu and Jean Michel Lecerf and Gérald Luc and Philippe Moulin and Jean Weissenbach and Annick Prat and Michel Krempf and Claudine Junien and Nabil G. Seidah and Catherine Boileau},
  journal={Nature Genetics},
Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9… 
Genetic heterogeneity of autosomal dominant hypercholesterolemia
Multiple reports give evidence for the existence of a greater level of genetic heterogeneity in ADH and the involvement of still unknown genes.
LDLR and ApoB are major genetic causes of autosomal dominant hypercholesterolemia in a Taiwanese population.
Familial hypercholesterolemia: clinical pearls
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  • Biology, Medicine
    Journal of Cardiology & Current Research
  • 2019
The three main genetic defects that lead to FH are defects in the LDL receptor gene, apolipoprotein B-100 (ApoB-100) gene4, and proprotein convertase subtilisin/Kexin type 9 (PCSK9) gene, which account for 60 to 80 percent of patients with definite FH.
Mutations in STAP1 Are Associated With Autosomal Dominant Hypercholesterolemia
A novel ADH locus at 4p13 is mapped and 4 variants in STAP1 that associate with ADH are identified that showed significantly higher plasma total cholesterol and low-density cholesterol levels compared with nonaffected relatives.
PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis
A large number of studies have focused on finding effective diagnostic and therapeutic methods based on PCSK9, one of the main pathogenic FH genes, whose contribution to FH deserves more explorative research.
APOE p.Leu167del mutation in familial hypercholesterolemia.
Apolipoprotein B100 Metabolism in Autosomal-Dominant Hypercholesterolemia Related to Mutations in PCSK9
The results showed that the effect of the S127R mutation of PCSK9 on plasma cholesterol homeostasis is mainly related to an overproduction of apolipoprotein B100.
A new PCSK9 gene promoter variant affects gene expression and causes autosomal dominant hypercholesterolemia.
PCSK9 is a rare cause of ADH in Spanish population and, up to what the authors know, none of the previously described mutations has been detected, but a new mutation is identified that could cause ADH by increasing the transcription of PCSK9.
To investigate genotype-phenotype correlations in FH carrying different mutations of the LDL-R gene, the frequency and spectrum of mutations causing FH in patients attending the different Italian lipid clinics was determined.
Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia
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  • Biology, Medicine
    Clinical genetics
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DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia and the notion that mutations within this gene cause autosomal dominant hypercholesterololemia is supported.


A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.
The results show that ADH is genetically more heterogeneous than conventionally accepted, and contains four candidate genes at 1p34.1-p32, outside the critical region, showing no identity with FH3.
Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.
The identification of a genetic region that appears to overlap the region found linked to severe hypercholesterolemia in French and Spanish families may provide important pathophysiological insights into new mechanisms that may lead to highly elevated LDL cholesterol and other associated dyslipidemic phenotypes.
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