PCSK9 – Homozygous Familial Hypercholesterolemia

PCSK9 gain-of-function variant c.94G>A (p.Glu32Lys) has been identified in HoFH patients, with 13 alleles among 41 homozygous familial hypercholesterolemia subjects [PMID:25014035]. However, most HoFH cases are due to LDLR defects and no independent multi-family segregation of PCSK9 homozygous variants has been reported, supporting a Limited clinical validity.

Functionally, PCSK9 promotes post-transcriptional degradation of the LDL receptor. In vitro overexpression and mouse models of PCSK9 gain-of-function mutants (e.g., p.Asp374Tyr) show enhanced LDLR turnover and elevated plasma LDL cholesterol, concordant with the human HoFH phenotype [PMID:15358785]. While these experimental data are robust, additional genetic and segregation studies are required to bolster the gene–disease association.

Key Take-home: PCSK9 gain-of-function mutations are a rare cause of HoFH and represent a therapeutic target for LDL-lowering interventions.

References

• Atherosclerosis • 2014 • Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. [PMID:25014035]
• The Journal of Biological Chemistry • 2004 • NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. [PMID:15358785]

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