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

Area of Science:

• Cardiovascular Disease Research
• Genetics and Genomics
• Animal Models

Background:

• N-ethyl-N-nitrosourea (ENU) mutagenesis is a method for generating novel genetic mutations.
• High-throughput phenotyping enables rapid assessment of numerous traits in model organisms.
• The LDL receptor (Ldlr) plays a critical role in cholesterol metabolism and cardiovascular health.

Purpose of the Study:

• To identify and characterize new mouse models of cardiovascular disease.
• To investigate the phenotypic differences between an ENU-induced Ldlr mutant (WHC) and a traditional Ldlr knockout (KO) mouse.
• To establish the WHC mouse as a tool for studying hyperlipidemia and atherosclerosis.

Main Methods:

• ENU mutagenesis was employed to induce mutations in mice.
• High-throughput phenotyping was used to screen for cardiovascular disease phenotypes.
• The identified C699Y mutation in the Ldlr gene defined the WHC mouse model.
• Phenotypic comparisons were made between WHC and Ldlr KO mice using an atherogenic diet.

Main Results:

• A novel loss-of-function mutation, C699Y, in the LDL receptor (Ldlr) gene was identified, creating the WHC mouse model.
• The WHC mouse exhibited accelerated atherosclerotic lesion formation compared to the Ldlr KO mouse.
• WHC mice showed reduced hepatosteatosis after short-term exposure to an atherogenic diet.
• The WHC mutation is on a pure C57BL/6J genetic background.

Conclusions:

• The WHC mouse represents a valuable new model for cardiovascular disease research, particularly for studying atherosclerosis.
• This model offers a unique platform for investigating genetic modifiers of hyperlipidemia and atherogenesis.
• Further genomic analysis may uncover novel sequence functions relevant to Ldlr regulation.