title: 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 inthis 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France; 2 Université Paris Descartes, 75006, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Marduel
authors.forename: Alain
authors.initials: A
authors.lastname: Carrié
authors.forename: Agnes
authors.initials: A
authors.lastname: Sassolas
authors.forename: Martine
authors.initials: M
authors.lastname: Devillers
authors.forename: Valérie
authors.initials: V
authors.lastname: Carreau
authors.forename: Mathilde
authors.initials: M
authors.lastname: Di Filippo
authors.forename: Danièle
authors.initials: D
authors.lastname: Erlich
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Alice
authors.initials: A
authors.lastname: Marques-Pinheiro
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Claudine
authors.initials: C
authors.lastname: Junien
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005602:France; D014644:Genetic Variation; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D008297:Male; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D011973:Receptors, LDL; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
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