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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:677.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Tommaso Fasano; Angelo B. Cefalù; Enza Di Leo; Davide Noto; Daniela Pollaccia; Letizia Bocchi; Vincenza Valenti; Renato Bonardi; Ornella Guardamagna; Maurizio Averna; Patrizia Tarugi

From the Department of Biomedical Sciences (T.F., E.D., L.B., P.T.), University of Modena and Reggio Emilia, Italy; Department of Clinical Medicine and Emerging Diseases (A.B.C., D.N., D.P., V.V., M.A.), University of Palermo, Italy; Division of Gastroenterology and Nutrition (R.B.), Molinette Hospital, Torino, Italy; Department of Pediatrics (O.G.), University of Torino, Italy.

Correspondence to Patrizia Tarugi, PhD, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, I-41100 Modena, Italy. E-mail tarugi{at}unimore.it; or Maurizio Averna, MD, Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy via del Vespro 141 I-90145 Palermo. E-mail avernam@unipa.it

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 African-Americans 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 (<5^th) percentile, 44 in the highest (>95^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.

Nonsense mutations in PCSK9 gene resulting in truncated PCSK9 protein were reported to be associated with reduced plasma LDL-C in blacks. Here we report a novel mutation producing a short truncated PCSK9 (Ala68fsLeu82X) in a kindred with familial hypobetalipoproteinemia and in a group of hypocholesterolemic white subjects.

Key Words: familial hypobetalipoproteinemia • hypocholesterolemia • loss of function mutation • PCSK9 gene

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