Abstract
Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France. Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly, 175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations: FH=PCSK9>FDB>‘Others’ genes. The respective contribution of each known gene to ADH in this French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands, no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes. © 2010 Wiley-Liss, Inc.
Highlights
Hypercholesterolemia is a major risk factor for atherosclerosis and its premature cardiovascular complications
The proportion of Autosomal Dominant Hypercholesterolemia (ADH) patients for whom the disease is not explained by a mutation in, either, LDLR, APOB, or proprotein convertase subtilisin-kexin type 9 (PCSK9) was estimated at 15.25 % (Varret et al 2008)
Within the 283 variations newly reported in this French population, 175 were novel mutational events (Tables 1, 2, and 3) and represent 45% (175/391) of the unique events we identified and 22% (222/1003) of probands with a variation in LDLR (1 with two new LDLR variants)
Summary
Hypercholesterolemia is a major risk factor for atherosclerosis and its premature cardiovascular complications. The first ADH causative gene identified was LDLR encoding the LDL receptor (Goldstein et al 1973) This disease was named FH for Familial Hypercholesterolemia (MIM# 606945) and its heterozygous prevalence was estimated at 1/500. A second gene was involved after the discovery of hypercholesterolemic patients with normal LDL receptor activity (Innerarity et al 1987) They carried a missense mutation (p.Arg3527Gln previously named p.Arg3500Gln) in APOB, encoding apolipoprotein B, the main ligand for the LDL receptor (Soria et al 1989). This new molecular disorder was called FDB for Familial Defective apolipoprotein B-100 (MIM# 144010) and its frequency has been estimated at 1/250 in Switzerland and 1/1250 in Northern Europe and the US (Rabès et al 2000). The aim of this study was to assess the molecular epidemiology of ADH in a representative French population
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