Key result
Novel PCSK9 missense variants reduce LDLR expression by up to ~15% versus wild type.
Why the study?
PCSK9 gain-of-function variants increase LDLR degradation and are potentially associated with Familial Hypercholesterolemia, but their effects on protein structure and LDLR interactions require elucidation.
May aid FH variant interpretation; leaves open clinical adoption without prospective validation.
PCSK9 gain-of-function (GOF) variants increase degradation of low-density lipoprotein receptor (LDLR) and are potentially associated with Familial Hypercholesterolemia (FH). This study aimed to explore the effects of PCSK9 missense variants on protein structure and interactions with LDLR using molecular modeling analyses and in vitro functional studies. Variants in FH-related genes were identified in a Brazilian FH cohort using an exon-target gene sequencing strategy. Eight PCSK9 missense variants in pro- [p.(E32K) and p.(E57K)], catalytic [p.(R237W), p.(P279T) and p.(A443T)], and C-terminal histidine-cysteine rich (CHR) [p.(R469W), p.(Q619P) and p.(R680Q)] domains were identified. Molecular dynamics analyses revealed that GOF variants p.(E32K) and p.(R469W) increased extreme motions in PCSK9 amino acid backbone fluctuations and affected Hbond and water bridge interactions between the pro-domain and CM1 region of the CHR domain. HEK293FT cells transfected with plasmids carrying p.(E32K) and p.(R469W) variants reduced LDLR expression (8.7 % and 14.8 %, respectively) compared to wild type (p < 0.05) but these GOF variants did not affect PCSK9 expression and secretion. The missense variants p.(P279T) and p.(Q619P) also reduced protein stability and altered Hbond interactions. In conclusion, PCSK9 p.(E32K), p.(R469W), p.(P279T) and p.(Q619P) variants disrupt intramolecular interactions that are essential for PCSK9 structural conformation and biological activity and may have a potential role in FH pathogenesis.
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Los et al. (2022) studied Familial Hypercholesterolemia (FH). PCSK9 missense variants p.(E32K) and p.(R469W) vs. Wild type was evaluated on LDLR expression (8.7% and 14.8% reduction, p=< 0.05). PCSK9 missense variants p.(E32K) and p.(R469W) reduced LDLR expression by 8.7% and 14.8%, respectively, compared to wild type (p < 0.05).
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