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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1337.)
© 2004 American Heart Association, Inc.

Editorials

The Mystery of PCSK9

Alan D. Attie

From the Department of Biochemistry, University of Wisconsin-Madison, Wisc.

Correspondence to Alan D. Attie, Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Dr, Madison, WI 53706-1569. Email attie@biochem.wisc.edu

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

Many of the most important breakthroughs in science do not come from hypothesis-driven experiments. Apart from serendipity, genetics is perhaps our best route to discoveries that elude our intuition. Genetics establishes a relationship between a gene and a phenotype, but does not necessarily provide mechanistic information. The emerging story of PCSK9 (originally called Narc-1) provides a case in point.

See page 1454

Last year, Abifadel and coworkers mapped a region on human chromosome 1 that segregated with autosomal dominant hypercholesterolemia in French families.¹ In a region containing 41 genes, they identified PCSK9 as a candidate gene. They found two missense mutations, S172R and F216L. Subsequently, a D374Ymutation was also detected in an unrelated Norwegian kindred² and in Utah pedigrees.³

PCSK9 is a member of the proprotein convertase family of proteases, most closely related to proteinase K.⁴ Apart from its expression in liver and neuronal tissue, it is also expressed in kidney mesenchymal cells and intestinal epithelia.⁴ It is induced during liver regeneration and neuronal differentiation.⁴ Its substrate specificity is different from many other proprotein convertases because it can cleave at nonbasic amino acids, a feature it shares with subtilisin-kexin isozyme-1/site 1 protease, although the latter enzyme requires a basic residue at position –4. Presently, the only known substrate of PCSK9 is itself; it autocatalytically cleaves its own propeptide between Gln-151 and Ser-152 (rat sequence).⁵

The PCSK9 gene is regulated by sterols. Indeed, dietary cholesterol potently suppresses its expression.⁶ Transgenic mice overexpressing the transactivation domain of SREBP-1a or SREBP-2 also showed . . . [Full Text of this Article]

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