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A PCSK9 variant and familial combined hyperlipidaemia
  1. M Abifadel1,2,
  2. L Bernier3,
  3. G Dubuc3,
  4. G Nuel4,
  5. J-P Rabès1,5,
  6. J Bonneau1,
  7. A Marques1,
  8. M Marduel1,
  9. M Devillers1,
  10. A Munnich1,
  11. D Erlich1,
  12. M Varret1,
  13. M Roy3,
  14. J Davignon3,
  15. C Boileau1,5
  1. 1
    Inserm, U781, Paris, France; APHP, hôpital Necker-Enfants malades, Paris, France; Faculté de médecine, Université Paris Descartes, Paris, France
  2. 2
    Faculté de pharmacie, Université Saint-Joseph, Beirut, Lebanon
  3. 3
    Institut de recherches cliniques, Montreal, Quebec, Canada
  4. 4
    MAP5, CNRS 8145, Université Paris Descartes, France
  5. 5
    Laboratoire de biochimie et de génétique moléculaire, hôpital Ambroise-Paré, APHP; Université Versailles–Saint-Quentin-en-Yvelines, UFR médicale Paris-Ile-de-France Ouest, France
  1. Dr M Abifadel, INSERM U781, Clinique Maurice Lamy, hôpital Necker-Enfants malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France; marianne.abi-fadel{at}


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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  • Funding: This work was supported by grants from Région Île-de-France, Institut National de la Santé et de la Recherche Médicale, GIS-institut des maladies rares, ANR (Agence Nationale de la Recherche) “Cardiovascular, Obesity, and Diabetes 2005”, ANR-Maladies Rares 2006, PHRC APHP AOM 06024, Université Paris Descartes, Conseil de la recherche de l’Université Saint-Joseph de Beyrouth, Franco-Lebanese program CEDRE, Pfizer Canada and FRSQ (Fonds de Recherche en Santé du Québec).

  • Competing interests: None declared.

  • Patient consent: Obtained.