Molecular spectrum of autosomal dominant hypercholesterolemia in France.
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.
Marduel
Marie
M
Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France; 2 Université Paris Descartes, 75006, Paris, France.
Carrié
Alain
A
Sassolas
Agnes
A
Devillers
Martine
M
Carreau
Valérie
V
Di Filippo
Mathilde
M
Erlich
Danièle
D
Abifadel
Marianne
M
Marques-Pinheiro
Alice
A
Munnich
Arnold
A
Junien
Claudine
C
Boileau
Catherine
C
Varret
Mathilde
M
Rabès
Jean-Pierre
JP
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
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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