title: An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia.
abstract: OBJECTIVE
  A substantial number of subjects with autosomal dominant hypercholesterolemia (ADH) do not have LDL receptor (LDLR) or apolipoprotein B (APOB) mutations. Some ADH subjects appear to hyperabsorb sterols from the intestine, thus we hypothesized that they could have variants of the Niemann-Pick C1-Like 1 gene (NPC1L1). NPC1L1 encodes a crucial protein involved in intestinal sterol absorption.
  
  
  RESULTS
  Four NPC1L1 variants (-133A>G, -18C>A, 1679C>G, 28650A>G) were analyzed in 271 (155 women and 116 men) ADH bearers without mutations in LDLR or APOB aged 30-70years and 274 (180 women and 94 men) control subjects aged 25-65years. The AC haplotype determined by the -133A>G and -18C>A variants was underrepresented in ADH subjects compared to controls (p=0.01). In the ADH group, cholesterol absorption/synthesis markers were significantly lower in AC homozygotes that in all others haplotypes. Electrophoretic mobility shift assay (EMSA) results revealed that the -133A-specific oligonucleotide produced a retarded band stronger than the -133G allele. Luciferase activity with NPC1L1 -133G variant was 2.5-fold higher than with the -133A variant.
  
  
  CONCLUSIONS
  The -133A>G polymorphism exerts a significant effect on NPC1L1 promoter activity. NPC1L1 promoter variants might explain in part the hypercholesterolemic phenotype of some subjects with nonLDLR/nonAPOB ADH.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Martín
authors.forename: M
authors.initials: M
authors.lastname: Solanas-Barca
authors.forename: A-L
authors.initials: AL
authors.lastname: García-Otín
authors.forename: S
authors.initials: S
authors.lastname: Pampín
authors.forename: M
authors.initials: M
authors.lastname: Cofán
authors.forename: E
authors.initials: E
authors.lastname: Ros
authors.forename: J-C
authors.initials: JC
authors.lastname: Rodríguez-Rey
authors.forename: M
authors.initials: M
authors.lastname: Pocoví
authors.forename: F
authors.initials: F
authors.lastname: Civeira
mesh_terms: D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000235:genetics; D002460:Cell Line; D002791:Cholesterol, Dietary / Q000493:pharmacokinetics; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005799:Genes, Dominant; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008156:Luciferases / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics; D013261:Sterols / Q000097:blood; D014162:Transfection
chemical_list: D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D008055:Lipids; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D011973:Receptors, LDL; D013261:Sterols; D008156:Luciferases