Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France

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.

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

“…The severity of the phenotype in ADH varies genetically with the type of mutation and the gene affected ( 8,9 ). LDLR is the gene most frequently associated with ADH and is also the best characterized.…”

“…LDLR is the gene most frequently associated with ADH and is also the best characterized. It is responsible for the disease called familial hypercholesterolemia (FH) (9)(10)(11). With the exception of a few founder populations, the spectrum of LDLR causing FH mutations is large.…”

“…ucl.ac.uk/ldlr/; and Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/]. France is among the most heterogeneous in the world: recent studies have identifi ed almost 400 mutations in more than 1,000 affected subjects ( 9,12 ).…”

Missense Mutation in the LDLR Gene: A Wide Spectrum in the Severity of Familial Hypercholesterolemia

“…Within the LDLR gene, 28.4% of the reported missense mutations are predicted to alter functional splicing signals. The missense mutation c.2140G>C (p.Glu714Gln) that was predicted to be benign with four prediction tools for substitutions (Polyphen*, SIFT*, Pmut* and SNPs3D*) was predicted to create the loss of the intron 14 donor splice site with either NetGene2* and NNSPLICE* prediction tools for splice site mutations (Marduel et al 2010). It is clear, however, that mRNA analyses are necessary to support these predictions, as performed for a small number of exonic substitutions.…”

“…The silent mutation p.Leu605Leu (c.1813C>T) was predicted to create a new donor splice site AGGT at position 1813 in exon 12. The use of this new donor site would lead to the substitution of leucine 605 by a threonine, the deletion of 11 amino acids (from Alanine 606 to Aspartate 616), a frameshift and the appearance of a premature termination 49 codons further on (Marduel et al 2010). The variant, c.621C>T (p.Gly207Gly), was found to be associated with altered splicing.…”