uAUG-creating variant in the LDLR gene causes mild Familial hypercholesterolemia

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Disease

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL cholesterol and early cardiovascular disease.
• Pathogenic variants in the LDLR gene are the primary cause of FH, impacting cholesterol metabolism.

Purpose of the Study:

• To investigate the functional impact of a novel LDLR 5'UTR variant identified in a family with mild FH.
• To evaluate the pathogenicity of previously reported LDLR 5'UTR variants.

Main Methods:

• Gene panel sequencing to identify variants.
• Luciferase assay to assess the functional impact of the novel variant on LDLR protein translation.
• Analysis of previously reported LDLR 5'UTR variants.

Main Results:

• A novel c.-8C>A variant in the LDLR 5'UTR was identified.
• This variant partially reduces LDLR protein translation efficiency by creating a new upstream start codon (uAUG).
• Previously reported variants (c.-5C>T, c.-14C>A, c.-23A>C) showed no significant effect on LDLR expression.

Conclusions:

• The novel LDLR 5'UTR variant contributes to a mild FH phenotype through reduced LDLR expression.
• Functional studies are crucial for classifying LDLR variants and diagnosing FH.
• 5'UTR variants can play a significant role in regulating LDLR expression and cholesterol levels.