Document Detail

Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.
MedLine Citation:
PMID:  15654334     Owner:  NLM     Status:  MEDLINE    
The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation. Mutations in the genes encoding either LDLR or its ligand (APOB) cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway, also cause hypercholesterolemia. These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia by reducing LDLR number. To test whether loss-of-function mutations in PCSK9 have the opposite effect, we sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL and found two nonsense mutations (Y142X and C679X). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (<0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol. These data indicate that common sequence variations have large effects on plasma cholesterol levels in selected populations.
Jonathan Cohen; Alexander Pertsemlidis; Ingrid K Kotowski; Randall Graham; Christine Kim Garcia; Helen H Hobbs
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-01-16
Journal Detail:
Title:  Nature genetics     Volume:  37     ISSN:  1061-4036     ISO Abbreviation:  Nat. Genet.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-01-28     Completed Date:  2005-03-01     Revised Date:  2007-06-06    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  161-5     Citation Subset:  IM    
Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines, Dallas, Texas 75390-9046, USA.
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MeSH Terms
African Continental Ancestry Group / genetics*
Cholesterol, LDL / blood*
Codon, Nonsense*
Middle Aged
Serine Endopeptidases / genetics*
Reg. No./Substance:
0/Cholesterol, LDL; 0/Codon, Nonsense; EC 3.4.21.-/PCSK9 protein, human; EC 3.4.21.-/Serine Endopeptidases
Comment In:
Nat Genet. 2007 Apr;39(4):439-40   [PMID:  17392801 ]
Erratum In:
Nat Genet. 2005 Mar;37(3):328

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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