Abstract 1022: Genetic Deficiency of Proprotein Convertase Subtilisin/Kexin 9: Identification of a Compound Heterozygote with no PCSK9
Circulating levels of low density lipoprotein cholesterol (LDL-C) play a crucial role in the pathogenesis of atherosclerosis. Selected missense mutations in PCSK9 cause hypercholesterolemia while nonsense mutations in the same gene cause hypocholesterolemia. Approximately 2% of African-Americans are heterozygous for a nonsense mutation in PCSK9 (Y142X or C679X). Heterozygosity for a nonsense mutation in this gene is associated with a 40% reduction in plasma LDL-C and an 88% reduction in cardiovascular disease. The levels of LDL-C vary from less than the 1st to the 50th percentile (compared to age- and sex-matched controls) among heterozygotes in the Dallas Heart Study. To determine the factors contributing to this variation, we conducted family studies. A PCSK9 −142X heterozygote with an LDL-C of 49 mg/dL was found to have a daughter who inherited the mutant allele and had an LDL-C of 14 mg/dL. Her father was also hypocholesterolemic (LDL-C of 39 mg/dL) but did not have a nonsense mutation in either PCSK9 allele. To determine if the daughter and her father had a different inactivating mutation in PCSK9, we sequenced the coding region of PCSK9 in the family. We identified an in-frame deletion in exon 3 of the gene, resulting in the loss of an arginine residue. Both the daughter and father were heterozygous for the deletion. Expression of the mutant PCSK9 allele in human embryonic kidney (HEK-293) cells demonstrated a failure of autocatalytic cleavage and secretion of the recombinant protein. Thus, the daughter is a compound heterozygote and has two inactivating mutations in PCSK9. Despite PCSK9 being expressed in the cerebellum, liver, small intestine and kidneys, the subject is a healthy, fertile, college-educated aerobics instructor. This is the first identified compound heterozygote with two inactivating mutations in PCSK9. The very low level of plasma LDL-C and apparent good health of this individual demonstrate that PCSK9 plays a major role in determining plasma levels of LDL-C and provides an attractive target for LDL-lowering therapy.