Document Detail

The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene.
MedLine Citation:
PMID:  19319977     Owner:  NLM     Status:  MEDLINE    
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.
Marianne Abifadel; Jean-Pierre Rabès; Sélim Jambart; Georges Halaby; Marie-Hélène Gannagé-Yared; Antoine Sarkis; Ghada Beaino; Mathilde Varret; Nabiha Salem; Sandra Corbani; Hermine Aydénian; Claudine Junien; Arnold Munnich; Catherine Boileau
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human mutation     Volume:  30     ISSN:  1098-1004     ISO Abbreviation:  Hum. Mutat.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-29     Completed Date:  2009-09-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E682-91     Citation Subset:  IM    
Copyright Information:
(c) 2009 Wiley-Liss, Inc.
Inserm, U781, Paris, France.
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MeSH Terms
Cholesterol, LDL / blood
Codon, Nonsense
Family Health
Hyperlipoproteinemia Type II
Lebanon / epidemiology
Mutation, Missense
Receptors, LDL / genetics
Serine Endopeptidases / genetics*,  physiology
Reg. No./Substance:
0/Cholesterol, LDL; 0/Codon, Nonsense; 0/Receptors, LDL; EC 3.4.21.-/PCSK9 protein, human; EC 3.4.21.-/Serine Endopeptidases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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