Table 1.
Loss-of-function mutations.
| Name of Mutation + Reference |
Cause and Consequences |
|---|---|
| A443T [121,122] | Presence of a novel PCSK9 O-glycosylation site in the hinge region that promotes furin-cleavage and generates lower circulating levels of LDL-C and lower levels of fasting glucose |
| A522T [98] T77I [98] V114A [98] P616L [98] |
Amino acid substitutions that cause hypocholesterolaemia |
| Ala68fsLeu82X [98] | Single nucleotide deletion in exon 1 that leads to a frameshift mutation that in turn causes the PCSK9 peptide to be shortened and not functional |
| C679X (rs28362286) [122,123,124,125] Y142X (rs67608943) [124] |
SNPs that lead to disruption in the folding of the protein and lower concentrations of Lp(a), LDLC, oxidised phospholipid (OxPL-ApoB), fasting glucose and glycated haemoglobin |
| G106R [126] | GG/AG genotype in exon 2 that leads to a mutation in the prodomain due to which PCSK9 fails to undergo autocatalytic cleavage and causes an increase in the amount of surface LDLR |
| G236S [119] Q152D [24] |
PCSK9 fails to exit the ER due to abnormal folding of the protein causing hypocholesterolaemia |
| N157K [126] | Causes hypocholesterolaemia, although studies do not exist on how the mutation causes the condition |
| N354I [119] | PCSK9 fails to undergo autocatalytic cleavage leading to the production of inactive protein |
| Arg46Leu [27,127] | Mutation in Exon 1 that leads to amino acid change of R46L and thereby to a lack of circulating PCSK9 |
| Asp301Gly [27] | Mutation in Exon 6 that leads to amino acid change of D301G and thereby to a lack of circulating PCSK9 |
| PCSK9-679X [97] | Elimination of final cysteine in the C-terminal domain that leads to PCSK9 failing to exit the ER after the protein folding is disrupted |
| PCSK9-FS [24] | C-terminal frameshift by which PCSK9 fails to exit the ER |
| Q152H (Gln152His) [24,128,129] | Amino acid substitution that prevents the autocatalytic processing of proPCSK9 inducing the reduction in circulating levels of PCSK9 and LDL-C, reduction in risk of developing CVD |
| R434W [103] | Alteration in the hinge region that impedes PCSK9 retention in the Trans-Golgi network that causes lower secretion levels of PCSK9 |
| rs11206510 [130,131,132] rs11583680 (A53V) [133] rs2479409 [134] rs151193009 (R93C) [100,134] |
SNPs which lead to reduced risk of CAD, peripheral artery disease, abdominal aortic aneurysm, type 2 diabetes, ischemic stroke, dementia, chronic obstructive pulmonary artery disease and cancer |
| rs11591147 (R46L) [126] | GT/TT genotype in exon 1 that leads to decreased levels of LDL-C and reduced risk of CVDs |
| S127R [118] | Mutation in pro-domain that causes low binding affinity to LDLR and increased catabolism of LDLC |
| S386A [126] R237W [126] |
Point mutations in the catalytic domain that lead to the failure of PCSK9 to undergo autocatalytic cleavage |