TY - JOUR
T1 - Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote
AU - Zhao, Zhenze
AU - Tuakli-Wosornu, Yetsa
AU - Lagace, Thomas A.
AU - Kinch, Lisa
AU - Grishin, Nicholas V.
AU - Horton, Jay D.
AU - Cohen, Jonathan C.
AU - Hobbs, Helen H.
N1 - Funding Information:
We thank Y. K. Ho for generating the antibodies used in these experiments. This work was supported by grants from the National Institute of Health (P01 HL20948), the Donald W. Reynolds Foundation, and the Perot Family Fund. T.A.L. is supported by the Natural Sciences and Engineering Research Council of Canada. Y.T.-W. is supported by the Stanley J. Sarnoff Endowment.
PY - 2006/9
Y1 - 2006/9
N2 - Elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) play a central role in the development of atherosclerosis. Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) that are associated with lower plasma levels of LDL-C confer protection from coronary heart disease. Here, we show that four severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wild-type PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the circulation and identified the first known individual who has no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for two inactivating mutations in PCSK9, had a strikingly low plasma level of LDL-C (14 mg/dL). The very low plasma level of 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.
AB - Elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) play a central role in the development of atherosclerosis. Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) that are associated with lower plasma levels of LDL-C confer protection from coronary heart disease. Here, we show that four severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wild-type PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the circulation and identified the first known individual who has no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for two inactivating mutations in PCSK9, had a strikingly low plasma level of LDL-C (14 mg/dL). The very low plasma level of 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.
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U2 - 10.1086/507488
DO - 10.1086/507488
M3 - Article
C2 - 16909389
AN - SCOPUS:33748661502
SN - 0002-9297
VL - 79
SP - 514
EP - 523
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -