title: A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol.
abstract: OBJECTIVE
  The PCSK9 gene, encoding a pro-protein convertase involved in posttranslational degradation of low-density lipoprotein receptor, has emerged as a key regulator of plasma low-density lipoprotein cholesterol. In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. The aim of this study was to assess whether loss of function mutations of PCSK9 were a cause of familial hypobetalipoproteinemia and a determinant of low-plasma low-density lipoprotein cholesterol in whites.
  
  
  RESULTS
  We sequenced PCSK9 gene in 18 familial hypobetalipoproteinemia subjects and in 102 hypocholesterolemic blood donors who were negative for APOB gene mutations known to cause familial hypobetalipoproteinemia. The PCSK9 gene variants found in these 2 groups were screened in 42 subjects in the lowest (<5th) percentile, 44 in the highest (>95th) percentile, and 100 with the average plasma cholesterol derived from general population. In one familial hypobetalipoproteinemia kindred and in 2 hypocholesterolemic blood donors we found a novel PCSK9 mutation in exon 1 (c.202delG) resulting in a truncated peptide (Ala68fsLeu82X). Two familial hypobetalipoproteinemia subjects and 4 hypocholesterolemic blood donors were carriers of the R46L substitution previously reported to be associated with reduced low-density lipoprotein cholesterol as well as other rare amino acid changes (T77I, V114A, A522T and P616L) not found in the other groups examined.
  
  
  CONCLUSIONS
  We discovered a novel inactivating mutation as well as some rare nonconservative amino acid substitutions of PCSK9 in white hypocholesterolemic individuals.
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, I-41100 Modena, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fasano
authors.forename: Angelo B
authors.initials: AB
authors.lastname: Cefalù
authors.forename: Enza
authors.initials: E
authors.lastname: Di Leo
authors.forename: Davide
authors.initials: D
authors.lastname: Noto
authors.forename: Daniela
authors.initials: D
authors.lastname: Pollaccia
authors.forename: Letizia
authors.initials: L
authors.lastname: Bocchi
authors.forename: Vincenza
authors.initials: V
authors.lastname: Valenti
authors.forename: Renato
authors.initials: R
authors.lastname: Bonardi
authors.forename: Ornella
authors.initials: O
authors.lastname: Guardamagna
authors.forename: Maurizio
authors.initials: M
authors.lastname: Averna
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarugi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood* / Q000235:genetics*; D018389:Codon, Nonsense; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000208:ethnology / Q000235:genetics*; D015994:Incidence; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012697:Serine Endopeptidases / Q000235:genetics*; D018709:Statistics, Nonparametric; D044465:White People / Q000235:genetics*
chemical_list: D008078:Cholesterol, LDL; D018389:Codon, Nonsense; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases