The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

Abstract

ABSTRACT:Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low-density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9). Familial hypercholesterolemia (FH) caused by mutation in the LDLR gene is the most frequent form of ADH. The incidence of FH is particularly high in the Lebanese population presumably as a result of a founder effect. In this study we characterize the spectrum of the mutations causing FH in Lebanon: we confirm the very high frequency of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH Lebanese probands recruited and identify other less frequent mutations in the LDLR. Finally, we show that the p.Leu21dup, an in frame insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9, known to be associated with lower LDL-cholesterol levels in general populations, is also associated with a reduction of LDL-cholesterol levels in FH patients sharing the p.C681X mutation in the LDLR. Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL-cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia.

Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia

“…However, several groups have reported on the effect of genetic variation in the PCSK9 gene on the phenotype of FH. ( 10,11,15 ) Abifadel and colleagues showed that individuals who coinherited pathogenic mutations in both PCSK9 and LDLR had higher LDL-C levels than did their relatives with either mutation alone ( 10 ). Conversely, Strom and colleagues studied the effect of a loss-of-function PCSK9 mutation, R46L, in FH ( 15 ).…”

“…The untreated individuals from the FH-low group (n = 94) had signifi cantly lower mean PCSK9 levels [152 (137-167) ng/ml] compared with untreated individuals from the FH-high group [n = 61, 186 (165-207) ng/ml, P = 0.010] and controls it binds to the hepatic LDLR and thereby directs it toward lysosomal degradation rather than to recycling to the cell membrane ( 8,9 ). The presence of a specifi c gain-of-function mutation in PCSK9 aggravates the hypercholesterolemia phenotype exerted by a concurrent pathogenic LDLR mutation ( 10,11 ). Conversely, low activity of PCSK9 could lead to increased presence of LDLR at the hepatic cell surface and, consequently, to increased clearance of plasma LDL-C.…”

Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia

“…However, the discovery of three nonpathogenic variants in our cohort clarifies only a small proportion (o2%) of the low LDL-C levels in mutation carriers. Other reasons for nonpenetrance may be related to healthy lifestyle or diet or to other mutations in the APOB and PCSK9 genes that neutralize the effect of the FH mutation [Abifadel et al, 2009;Fouchier et al, 2005b;Leren and Berge, 2008;van der Graaf et al, 2008].…”

hypercholestérolémie familiale au Saguenay-Lac-Saint-Jean :

“…Le premier consiste en des mutations faux-sens de PCSK9 comme S127R et F216L (Abifadel et al, 2003) et D374Y (Sun et al, 2005) qui peuvent causer une augmentation de Pactivité du précurseur PCSK9 et aggraver le phénotype clinique des patients porteurs de mutations LDLR (Pisciotta et al, 2006); et le second comprend des mutations nonsens dans le gène PCSK9 comme Y142X et C679X (Cohen et al, 2005) et qui sont inversement liées à l'hypocholestérolémie car elles entraînent une réduction dans l'activité PCSK9 (Leren, 2004;Timms et al, 2004;Allard et al, 2005;Cohen et al, 2006;Abifadel et al, 2009). …”