title: PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia.
abstract: OBJECTIVE
  Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central player in the regulation of cholesterol homeostasis, increasing the low-density lipoprotein (LDL) receptor degradation. Our study aimed at exploring the pathogenic consequences in vivo and in vitro of a PCSK9 prodomain mutation found in a family with hypobetalipoproteinemia (FHBL).
  
  
  RESULTS
  A white 49-year-old diabetic man had profound FBHL (LDLC: 16 mg/dL) whereas his daughter and sister displayed a milder phenotype (LDLC 44 mg/dL and 57 mg/dL, respectively), all otherwise healthy with a normal liver function. A monoallelic PCSK9 double-mutant R104C/V114A cosegregated with FBHL, with no mutation found at other FHBL-causing loci. A dose-effect was also found in FBHL relatives for plasma APOB and PCSK9 (very-low to undetectable in proband, approximately 50% decreased in sister and daughter) and LDL catabolic rate (256% and 88% increased in proband and daughter). Transient transfection in hepatocytes showed severely impaired processing and secretion of the double mutant which acted as a dominant negative over secretion of wild-type PCSK9.
  
  
  CONCLUSIONS
  These results show that heterozygous PCSK9 missense mutations may associate with profound hypobetalipoproteinemia and constitute the first direct evidence in human that decrease of plasma LDLC concentrations associated to PCSK9 LOF mutations are attributable to an increased clearance rate of LDL.
authors.affiliation: INSERM, U915, Nantes F-44000, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.forename: Khadija
authors.initials: K
authors.lastname: Ouguerram
authors.forename: Yassine
authors.initials: Y
authors.lastname: Zaïr
authors.forename: Raphael
authors.initials: R
authors.lastname: Guerois
authors.forename: Cédric
authors.initials: C
authors.lastname: Langhi
authors.forename: Sanae
authors.initials: S
authors.lastname: Kourimate
authors.forename: Isabelle
authors.initials: I
authors.lastname: Benoit
authors.forename: Cédric
authors.initials: C
authors.lastname: Le May
authors.forename: Constance
authors.initials: C
authors.lastname: Gayet
authors.forename: Khaldia
authors.initials: K
authors.lastname: Belabbas
authors.forename: Fabienne
authors.initials: F
authors.lastname: Dufernez
authors.forename: Maud
authors.initials: M
authors.lastname: Chétiveaux
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarugi
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.forename: Pascale
authors.initials: P
authors.lastname: Benlian
authors.forename: Philippe
authors.initials: P
authors.lastname: Costet
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001055:Apolipoproteins B / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D005799:Genes, Dominant; D022781:Hepatocytes / Q000201:enzymology; D006579:Heterozygote; D006801:Humans; D052476:Hypobetalipoproteinemia, Familial, Apolipoprotein B / Q000097:blood / Q000201:enzymology / Q000235:genetics; D006995:Hypobetalipoproteinemias / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000097:blood* / Q000172:deficiency / Q000235:genetics*; D014162:Transfection
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011994:Recombinant Proteins; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases