This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jirholt, P. Articles by Borén, J. Search for Related Content PubMed PubMed Citation Articles by Jirholt, P. Articles by Borén, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Genetics Home Reference Related Collections Pathophysiology Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1334.)
© 2004 American Heart Association, Inc.

Editorials

How Does Mutant Proprotein Convertase Neural Apoptosis-Regulated Convertase 1 Induce Autosomal Dominant Hypercholesterolemia?

Pernilla Jirholt; Martin Adiels; Jan Borén

From the Wallenberg Laboratory for Cardiovascular Research and the Cardiovascular Institute, The Sahlgrenska Academy at Göteborg University, 413-45 Göteborg, Sweden.

Correspondence to Jan Borén, MD, PhD, Wallenberg Laboratory, Sahlgrenska University Hospital S-413-45 Göteborg, Sweden. E-mail Jan.Boren@wlab.gu.se

An extract of the first 250 words of the full text is provided, because this article has no abstract.

In the secretory pathway of the cell, many biologically inactive precursor proteins are processed by limited proteolysis to produce biologically active peptides and proteins. The enzymes that perform these cleavages are referred to as subtilisin-like proprotein convertases (SPCs).¹ Seven members of the SPC family are known. One, the subtilisin kexin isoenzyme-1/site-1-protease (SKI-1/S1P), has a key role in cholesterol homeostasis through processing of the sterol regulatory element-binding proteins (SREBPs).^2,3 Another member of the SPC family, neural apoptosis-regulated convertase 1 (NARC-1), which was recently linked to a novel form of autosomal dominant familial hypercholesterolemia,⁴ is downregulated by cholesterol and upregulated by SREBP-2.^5,6 These findings indicate that NARC-1, like SKI-1/S1P, is an important player in lipid metabolism.

See page 1448

Autosomal dominant hypercholesterolemia (ADH) is characterized by an increase in low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. ADH is associated mainly with mutations in the genes encoding the LDL receptor (ie, familial hypercholesterolemia)⁷ and apolipoprotein B100 (apoB100; ie, familial defective apoB100).⁸ These mutations directly or indirectly reduce the ability of the LDL receptor to mediate tendocytosis of plasma lipoproteins containing apoB or apoE.

Analysis of large cohorts of patients with heterozygous familial hypercholesterolemia indicated that inherited defects in genes other than those encoding the LDL receptor and apoB can cause hypercholesterolemia. This was first proven when Garcia et al showed that mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia.^9,10 A novel locus associated with ADH has been mapped to 1p34.1-p32.^4,11 To identify this locus, Abifadel et al performed . . . [Full Text of this Article]

This article has been cited by other articles:

				E. N. Hampton, M. W. Knuth, J. Li, J. L. Harris, S. A. Lesley, and G. Spraggon The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain PNAS, September 11, 2007; 104(37): 14604 - 14609. [Abstract] [Full Text] [PDF]

				X.-M. Sun, E. R. Eden, I. Tosi, C. K. Neuwirth, D. Wile, R. P. Naoumova, and A. K. Soutar Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia Hum. Mol. Genet., May 1, 2005; 14(9): 1161 - 1169. [Abstract] [Full Text] [PDF]