A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Disease Research

Background:

• Familial hypercholesterolaemia (FH) is a genetic disorder leading to high LDL cholesterol levels.
• Mutations in the LDL receptor gene (LDLR) are a primary cause of FH, impairing cholesterol clearance.
• Early identification of FH is crucial for reducing premature coronary heart disease risk through lifestyle changes and medication.

Observation:

• A specific nucleotide substitution (CGG to AGG) in exon 9 of the LDLR gene was identified.
• This substitution was initially considered a silent polymorphism.
• Analysis of patient mRNA revealed the mutation creates a new splice site.

Findings:

• The new splice site leads to the exclusion of the natural splice site during mRNA processing.
• A 31 bp deletion occurs in the mRNA sequence.
• This deletion is predicted to cause premature termination of the LDL receptor protein synthesis.

Implications:

• Genetic diagnosis of FH solely based on genomic DNA sequence may be insufficient.
• Distinguishing between silent polymorphisms and functional mutations is critical for accurate FH diagnosis.
• This highlights the importance of mRNA analysis in genetic testing for inherited cardiovascular conditions.