A novel missense mutation C127R (FH Zagreb) in the LDL-receptor gene

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Disease

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein (LDL) cholesterol.
• Mutations in the LDL receptor (LDLR) gene are a primary cause of FH.
• Identifying specific mutations is crucial for genetic diagnosis and understanding disease prevalence.

Purpose of the Study:

• To identify novel mutations in the LDLR gene responsible for familial hypercholesterolemia.
• To characterize the prevalence of specific LDLR mutations in a Croatian FH population.

Main Methods:

• Single-strand conformation polymorphism (SSCP) analysis was used to screen for mutations in exon 4 of the LDLR gene.
• DNA sequencing was employed to confirm and characterize identified mutations.
• Restriction endonuclease analysis (Dsa I) was used to validate the novel C127R mutation.

Main Results:

• Two mutations, C127R (FH Zagreb) and D200G (FH Padova), were identified in exon 4 of the LDLR gene.
• The C127R mutation, a novel T-to-C substitution at nucleotide 442, results in an amino acid change from Cysteine to Arginine at codon 127.
• The D200G mutation, an A-to-G substitution at nucleotide 662, changes Aspartic acid to Glycine at codon 200.
• These two mutations account for approximately 0.7% of FH cases in the screened Croatian population.

Conclusions:

• A novel mutation, C127R, in the LDLR gene causing familial hypercholesterolemia has been identified and characterized.
• The identified mutations, C127R and D200G, contribute to the genetic landscape of familial hypercholesterolemia in Croatia.
• This study highlights the importance of mutation screening for understanding FH etiology and epidemiology.