A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

Abstract

Objectives-The PCSK9 gene, encoding a pro-protein convertase involved in posttranslational degradation of low-density lipoprotein receptor, has emerged as a key regulator of plasma low-density lipoprotein cholesterol. In AfricanAmericans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. The aim of this study was to assess whether loss of function mutations of PCSK9 were a cause of familial hypobetalipoproteinemia and a determinant of low-plasma low-density lipoprotein cholesterol in whites. Methods and Results-We sequenced PCSK9 gene in 18 familial hypobetalipoproteinemia subjects and in 102 hypocholesterolemic blood donors who were negative for APOB gene mutations known to cause familial hypobetalipoproteinemia. The PCSK9 gene variants found in these 2 groups were screened in 42 subjects in the lowest (Ͻ5 th ) percentile, 44 in the highest (Ͼ95 th ) percentile, and 100 with the average plasma cholesterol derived from general population. In one familial hypobetalipoproteinemia kindred and in 2 hypocholesterolemic blood donors we found a novel PCSK9 mutation in exon 1 (c.202delG) resulting in a truncated peptide (Ala68fsLeu82X). Two familial hypobetalipoproteinemia subjects and 4 hypocholesterolemic blood donors were carriers of the R46L substitution previously reported to be associated with reduced low-density lipoprotein cholesterol as well as other rare amino acid changes (T77I, V114A, A522T and P616L) not found in the other groups examined. Conclusions-We discovered a novel inactivating mutation as well as some rare nonconservative amino acid substitutions of PCSK9 in white hypocholesterolemic individuals.

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

“…Rare amino acid changes, p.T77I, p.V114A, p.A522 T, and p.P616L of PCSK9, have been found in hypocholesterolemic blood donors recruited in Sicily (with plasma cholesterol values below the 2nd percentile of the population), and absent in a group of 100 normocholesterolemic controls derived from the general population [Fasano et al, 2007]. Furthermore the threonine, valine, and alanine, at positions 77, 114, and 522, respectively, are conserved among mammalian species and are located in highly-conserved regions of the gene, suggesting that their nonconservative substitution might have some biological effect [Fasano et al, 2007].…”

“…The p.R46L and p.A443T variants are associated with lower LDL-C levels in population studies [Kotowski et al, 2006;Berge et al, 2006;Fasano et al, 2007;Scartezini et al, 2007]; however, they might be found also in normo-or hypercholesterolemic individuals due to other genetic or environmental factors influencing cholesterol levels [Abifadel et al, 2003;Allard et al, 2005;Kotowski et al, 2006].…”

“…Another variant, p.R93C, that is also specific of the Japanese population, was found in either hypercholesterolemic or hypocholesterolemic patients but was significantly associated with low LDL-C levels [Miyake et al, 2008]. Finally, two nonsense mutants, p.A68fsL82X and p.W428X, have been reported in Sicilian and Japanese hypocholesterolemic patients [Fasano et al, 2007;Miyake et al, 2008], respectively.…”

“…Furthermore the threonine, valine, and alanine, at positions 77, 114, and 522, respectively, are conserved among mammalian species and are located in highly-conserved regions of the gene, suggesting that their nonconservative substitution might have some biological effect [Fasano et al, 2007].…”

“…This 32-year-old African American woman with an LDL-C level of only 14 mg/dl, was apparently healthy, fertile, normotensive, with grossly normal hepatic, neuronal, and renal function tests [Zhao et al, 2006;Horton et al, 2007]. In one Sicilian hypobetalipoproteinemia kindred, a deletion in exon 1 (c.202delG) was found, which causes a frameshift in mRNA leading to a premature stop codon (p.A68fsL82X) [Fasano et al, 2007]. The proband and his father were overweight Caucasian heterozygous carriers of this mutation with low LDL-C levels and fatty liver.…”