title: Characterization of novel mutations in the catalytic domain of the PCSK9 gene.
abstract: OBJECTIVE
  To expand our understanding of the structure and function of proprotein convertase subtilisin/kexin type 9 (PCSK9) by studying how naturally occurring mutations in PCSK9 disrupt the function of PCSK9.
  
  
  METHODS
  Mutations in PCSK9 were identified by sequencing of DNA from subjects with hypo- or hypercholesterolemia. The effect of the identified mutations on the autocatalytic cleavage and secretion of PCSK9, as well as the effect on PCSK9-mediated degradation of the low density lipoprotein receptors, were determined in HepG2 or HEK293 cells transiently transfected with mutant PCSK9-containing plasmids. The findings were collated to the clinical characteristics of the subjects possessing these mutations, and the phenotypic effects were analysed in terms of available structural data for PCSK9.
  
  
  RESULTS
  Five novel mutations in PCSK9 were identified. Mutation R215H was a gain-of-function mutation which causes hypercholesterolemia. Mutation G236S and N354I were loss-of-function mutations due to failure to exit the endoplasmic reticulum or failure to undergo autocatalytic cleavage, respectively. Mutations A245T and R272Q were most likely normal genetic variants. By comparing the number of patients with gain-of-function mutations in PCSK9 with the number of familial hypercholesterolemia heterozygotes among subjects with hypercholesterolemia, the prevalence of subjects with gain-of-function mutations in PCSK9 in Norway can be estimated to one in 15,000.
  
  
  CONCLUSIONS
  This study has provided novel information about the structural requirements for the normal function of PCSK9. However, more studies are needed to determine the mechanisms by which gain-of-function mutations in PCSK9 cause hypercholesterolemia.
authors.affiliation: Department of Medical Genetics, Medical Genetics Laboratory, Rigshospitalet-Radiumhospitalet Medical Centre, Oslo, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Cameron
authors.forename: O L
authors.initials: OL
authors.lastname: Holla
authors.forename: J K
authors.initials: JK
authors.lastname: Laerdahl
authors.forename: M A
authors.initials: MA
authors.lastname: Kulseth
authors.forename: T
authors.initials: T
authors.lastname: Ranheim
authors.forename: T
authors.initials: T
authors.lastname: Rognes
authors.forename: K E
authors.initials: KE
authors.lastname: Berge
authors.forename: T P
authors.initials: TP
authors.lastname: Leren
mesh_terms: D000328:Adult; D020134:Catalytic Domain / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009664:Norway; D011237:Predictive Value of Tests; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases