A PCSK9 variant and familial combined hyperlipidaemia

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Disease

Background:

• The discovery of PCSK9 gene mutations in 2003 identified a key regulator of low-density lipoprotein cholesterol (LDL-C).
• Gain-of-function PCSK9 mutations elevate LDL-C by reducing LDL receptors, while loss-of-function variants decrease LDL-C and heart disease risk.

Purpose of the Study:

• To investigate the role of PCSK9 variants in familial combined hyperlipidaemia (FCHL).
• To identify novel mutations in the PCSK9 gene associated with dyslipidaemia.

Main Methods:

• Screening of 25 families with FCHL for PCSK9 gene mutations.
• Genotyping and analysis of lipid profiles in affected individuals.

Main Results:

• An insertion mutation (p.L21tri or p.L15_L16ins2L) was identified in the PCSK9 signal peptide in two FCHL families.
• This mutation was associated with elevated total cholesterol and LDL-C levels.
• The p.L21tri mutation was also found in a patient with familial hypercholesterolaemia and her father.

Conclusions:

• PCSK9 variants, including the novel p.L21tri mutation, may contribute to the FCHL phenotype.
• These findings highlight the importance of considering PCSK9 in the genetic basis of complex lipid disorders like FCHL.