Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote

Am J Hum Genet. 2006 Sep;79(3):514-23. doi: 10.1086/507488. Epub 2006 Jul 18.


Elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) play a central role in the development of atherosclerosis. Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) that are associated with lower plasma levels of LDL-C confer protection from coronary heart disease. Here, we show that four severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wild-type PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the circulation and identified the first known individual who has no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for two inactivating mutations in PCSK9, had a strikingly low plasma level of LDL-C (14 mg/dL). The very low plasma level of LDL-C and apparent good health of this individual demonstrate that PCSK9 plays a major role in determining plasma levels of LDL-C and provides an attractive target for LDL-lowering therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Cells, Cultured
  • Child, Preschool
  • Cholesterol, LDL / blood*
  • Cholesterol, LDL / metabolism
  • Female
  • Heterozygote
  • Humans
  • Immunoprecipitation
  • Male
  • Middle Aged
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Protein Conformation
  • Protein Folding
  • Protein Transport
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Serine Endopeptidases / blood*
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism


  • Cholesterol, LDL
  • Recombinant Proteins
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases