HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Peterson, J. Articles by Brunzell, J. D. Search for Related Content PubMed PubMed Citation Articles by Peterson, J. Articles by Brunzell, J. D. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 43, 398-406, March 2002
Copyright © 2002 by Lipid Research, Inc.

Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene

Correspondence to: John D. Brunzell, To whom correspondence should be addressed., brunzell{at}u.washington.edu (E-mail)

Missense mutations in exon 5 of the LPL gene are the most common reported cause of LPL deficiency. Exon 5 is also the region with the strongest homology to pancreatic and hepatic lipase, and is conserved in LPL from different species. Mutant LPL proteins from post-heparin plasma from patients homozygous for missense mutations at amino acid positions 176, 188, 194, 205, and 207, and from COS cells transiently transfected with the corresponding cDNAs were quantified and characterized, in an attempt to determine which aspect of enzyme function was affected by each specific mutation. All but one of the mutant proteins were present, mainly as partially denatured LPL monomer, rendering further detailed assessment of their catalytic activity, affinity to heparin, and binding to lipoprotein particles difficult. However, the fresh unstable Gly¹⁸⁸Glu LPL and the stable Ile¹⁹⁴Thr LPL, although in native conformation, did not express lipase activity. It is proposed that many of the exon 5 mutant proteins are unable to achieve or maintain native dimer conformation, and that the Ile¹⁹⁴Thr substitution interferes with access of lipid substrate to the catalytic pocket.

These results stress the importance of conformational evaluation of mutant LPL. Absence of catalytic activity does not necessarily imply that the substituted amino acid plays a specific direct role in catalysis. — Peterson, J., A. F. Ayyobi, Y. Ma, H. Henderson, M. Reina, S. S. Deeb, S. Santamarina-Fojo, M. R. Hayden, and J. D. Brunzell. Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene. J. Lipid Res. 2002. 43: 398–406.

Supplementary key words: LPL deficiency, triglyceride, heparin, LPL gene, LPL mass

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. Dorfmeister, W.W. Zeng, A. Dichlberger, S.K. Nilsson, F.G. Schaap, J.A. Hubacek, M. Merkel, J.A. Cooper, A. Lookene, W. Putt, et al. Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1866 - 1871. [Abstract] [Full Text] [PDF]

				H. H. Wittrup, R. V. Andersen, A. Tybjaerg-Hansen, G. B. Jensen, and B. G. Nordestgaard Combined Analysis of Six Lipoprotein Lipase Genetic Variants on Triglycerides, High-Density Lipoprotein, and Ischemic Heart Disease: Cross-Sectional, Prospective, and Case-Control Studies from the Copenhagen City Heart Study J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1438 - 1445. [Abstract] [Full Text] [PDF]

				A. Lookene, L. Zhang, M. Hultin, and G. Olivecrona Rapid Subunit Exchange in Dimeric Lipoprotein Lipase and Properties of the Inactive Monomer J. Biol. Chem., November 26, 2004; 279(48): 49964 - 49972. [Abstract] [Full Text] [PDF]