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Journal of Lipid Research, Vol. 49, 2452-2462, November 2008 A new mouse mutant for the LDL receptor identified using ENU mutagenesis*
* The Jackson Laboratory, Bar Harbor, ME 04609 * 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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