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Review Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. 2009
Abifadel M, Rabès JP, Devillers M, Munnich A, Erlich D, Junien C, Varret M, Boileau C. · Institut Nationale de la Santé et de la Recherche Médicale (INSERM), U781, Paris, France. · Hum Mutat. · Pubmed #19191301 No free full text.
Abstract: 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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Article A PCSK9 variant and familial combined hyperlipidaemia. 2008
Abifadel M, Bernier L, Dubuc G, Nuel G, Rabès JP, Bonneau J, Marques A, Marduel M, Devillers M, Munnich A, Erlich D, Varret M, Roy M, Davignon J, Boileau C. · INSERM U781, Clinique Maurice Lamy, hôpital Necker-Enfants malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France. · J Med Genet. · Pubmed #18708425 No free full text.
Abstract: BACKGROUND: Our discovery in 2003 of the first mutations of PCSK9 gene causing autosomal dominant hypercholesterolaemia (ADH) shed light on an unknown factor that strongly influences the level of circulating low density lipoprotein cholesterol (LDL-C). PCSK9 gain of function mutations cause hypercholesterolaemia by a reduction of LDL receptor levels, while PCSK9 loss of function variants are associated with a reduction of LDL-C values and a decreased risk of coronary heart disease. METHODS AND RESULTS: We report an insertion of two leucines (p.L21tri also designated p.L15_L16ins2L) in the leucine stretch of the signal peptide of PCSK9 that is found in two of 25 families with familial combined hyperlipidaemia (FCHL). This mutant is associated with high total cholesterol and LDL-C values in these families and is found also in a patient with familial hypercholesterolaemia and her father. CONCLUSION: PCSK9 variants might contribute to FCHL phenotype and are to be taken into consideration in the study of this complex and multigenic disease with other genes implicated in dyslipidaemia.
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