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Journal of Lipid Research, Vol. 49, 2452-2462, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

A new mouse mutant for the LDL receptor identified using ENU mutagenesis^*

Karen L. Svenson^2,*, Nadav Ahituv^1,, Rebecca S. Durgin^*, Holly Savage^*, Phyllis A. Magnani^*, Oded Foreman^*, Beverly Paigen^* and Luanne L. Peters^*

^* The Jackson Laboratory, Bar Harbor, ME 04609
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
¹ Present address: Department of Biopharmaceutical Sciences and Institute for Human Genetics, University of California San Fransisco, San Francisco, CA 94143.

^* This work was supported by National Heart, Lung, and Blood Institute programs for genomic applications, Grant HL-66611.

Published, JLR Papers in Press, July 15, 2008.

² To whom correspondence should be addressed. e-mail: ksven{at}jax.org

In an effort to discover new mouse models of cardiovascular disease using N-ethyl-N-nitrosourea (ENU) mutagenesis followed by high-throughput phenotyping, we have identified a new mouse mutation, C699Y, in the LDL receptor (Ldlr), named wicked high cholesterol (WHC). When WHC was compared with the widely used Ldlr knockout (KO) mouse, notable phenotypic differences between strains were observed, such as accelerated atherosclerotic lesion formation and reduced hepatosteatosis in the ENU mutant after a short exposure to an atherogenic diet. This loss-of-function mouse model carries a single base mutation in the Ldlr gene on an otherwise pure C57BL/6J (B6) genetic background, making it a useful new tool for understanding the pathophysiology of atherosclerosis and for evaluating additional genetic modifiers regulating hyperlipidemia and atherogenesis. Further investigation of genomic differences between the ENU mutant and KO strains may reveal previously unappreciated sequence functionality.

Supplementary key words N-ethyl-N-nitrosourea • atherosclerosis • hyperlipidemia • high-throughput phenotyping

Abbreviations: Apoe, apolipoprotein E; ATH, atherogenic; ENU, N-ethyl-N-nitrosourea; FH, familial hypercholesterolemia; G3, three-generation; KO, knockout; Ldlr, LDL receptor; WHC, wicked high cholesterol

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