A PCSK9 variant and familial combined hyperlipidaemia

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.