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A PCSK9 variant and familial combined hyperlipidemia
  1. Marianne Abifadel (abifadel{at}necker.fr)
  1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
    1. Lise Bernier
    1. Institut de recherche Clinique, Montreal, Canada
      1. Geneviève Dubuc
      1. Institut de recherche Clinique, Montreal, Canada
        1. Gregory Nuel
        1. MAP5, CNRS 8145, Université Paris Descartes, France
          1. Jean Pierre Rabès
          1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
            1. Jessica Bonneau
            1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
              1. Alice Marques
              1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
                1. Marie Marduel
                1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
                  1. Martine Devillers
                  1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
                    1. Daniele Erlich
                    1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
                      1. Mathilde Varret
                      1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France
                        1. Madeleine Roy
                        1. Institut de recherche Clinique, Montreal, Canada
                          1. Jean Davignon
                          1. Institut de recherche Clinique, Montreal, Canada
                            1. Catherine Boileau
                            1. INSERM U781 , Clinique Maurice Lamy, hôpital Necker-Enfants malades, Paris, France

                              Abstract

                              Our discovery in 2003 of the first mutations of PCSK9 gene causing autosomal dominant hypercholesterolemia (ADH) shed the light on an unknown actor that strongly influences the level of circulating low density lipoprotein cholesterol (LDL-C). PCSK9 gain of function mutations cause hypercholesterolemia by a reduction of LDL receptor levels; while PCSK9 loss of function variants are associated with a reduction of LDL-C levels and a decreased risk of coronary heart disease. Here, we report an insertion of 2 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 Hyperlipidemia (FCHL). This mutant is associated with high total cholesterol and LDL-C levels in these families and is found also in a patient with familial hypercholesterolemia and her father. Thus, 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 dyslipidemia.

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