PCSK9 gene LOF mutations and polymorphisms causing hypocholesterolemia
| Protein Position | Nucleotide Position | Exon | Geographical Origin of Patients | Clinical Features | References |
|---|---|---|---|---|---|
| Leucine stretch: p.L21dup also designated p.L15_L16insL | c.dup61_63CTG also designated c.43_44insCTG | 1 | Frequently found in several populations | Decrease of LDL-c levels of 10–15 mg/dL | Abifadel et al., 2003; Chen et al., 2005; Yue et al., 2006 |
| p.Arg46Leu | c.137 G > T | 1 | Frequently found in several populations | Associated with a 15% reduction of LDL-c and 47% of CHD in whites; reduction of the risk of early-onset myocardial infraction | Abifadel et al., 2003; Cameron et al., 2006; Cohen et al., 2006; Kotowski et al., 2006; Scartezini et al., 2007; Dewpura et al., 2008; Kathiresan et al., 2008 |
| p.A68fsL82X | c.202delG | 1 | Sicily: 1 kindred | Fatty liver in the proband and his father but not in blood donors from healthy carriers | Fasano et al., 2007 |
| 2 hypocholesterolemic blood donors | |||||
| p.Thr77Ile | c.230C > T | 2 | Sicily | Hypocholesterolemic blood donors | Fasano et al., 2007 |
| p.Arg104Cys | c.310C > T | 2 | French | R104C/V114A segregates with FHBL; dominant negative when associated with c.341T > C (p.Val114Ala) on the same allele: impairs processing and secretion of wild-type PCSK9 in liver; low plasma PCSK9 concentration, LDL clearance rate >200% of normal | Cariou et al., 2009 |
| p.Gly106Arg | c.316G > A | 2 | 1 Norwegian family | Hypocholesterolemic subjects; low autocatalytic cleavage | Berge et al., 2006; Nassoury et al., 2007 |
| p.Val114Ala | c.341T > C | 2 | Sicily | Hypocholesterolemic blood donors | Fasano et al., 2007 |
| p.Tyr142X | c.426C > G | 3 | 0.4% DHS1 | Reduction of LDL-c levels of 40% and CHD of 88% | Cohen et al., 2006; Kotowski et al., 2006 |
| 0.8% ARIC2 of African Americans | |||||
| p.Q152H | c.436G > C | 3 | French-Canadian | Reduction of PCSK9 levels by 79% and LDL-c by 48% | Mayne et al., 2011 |
| p.Leu253Phe | c.757C > T | 5 | Black American and Hispanic | Hypocholesterolemic | Kotowski et al., 2006 |
| p.Trp428X | c.1284G > A | 8 | 1 Japanese subject | Hypocholesterolemic: complete LOF due to early termination | Miyake et al., 2008 |
| p.Ala522Thr | c.1564G > A | 10 | Sicily | Hypocholesterolemic blood donors | Fasano et al., 2007 |
| p.Gln554Glu | c.1660C > G | 10 | Black American, Hispanic | Mild reduction in LDL-c levels | Kotowski et al., 2006 |
| p.Pro616Leu | c.1847C > T | 11 | Sicily | Hypocholesterolemic blood donors | Fasano et al., 2007 |
| p.Cys679X | c.2037C > A | 12 | 1.4% (DHS); 1.8% (ARIC) | Reduction of LDL-c levels of 40% and CHD of 88% for heterozygous carriers | Cohen et al., 2006; Kotowski et al., 2006 |
| Blacks. <0.1% of White Americans |
CHD, coronary heart disease; FHBL, familial hypobetalipoproteinemia; LDL-c, low-density lipoprotein cholesterol; LOF, loss-of-function.