PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia.
OBJECTIVE
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central player in the regulation of cholesterol homeostasis, increasing the low-density lipoprotein (LDL) receptor degradation. Our study aimed at exploring the pathogenic consequences in vivo and in vitro of a PCSK9 prodomain mutation found in a family with hypobetalipoproteinemia (FHBL).


RESULTS
A white 49-year-old diabetic man had profound FBHL (LDLC: 16 mg/dL) whereas his daughter and sister displayed a milder phenotype (LDLC 44 mg/dL and 57 mg/dL, respectively), all otherwise healthy with a normal liver function. A monoallelic PCSK9 double-mutant R104C/V114A cosegregated with FBHL, with no mutation found at other FHBL-causing loci. A dose-effect was also found in FBHL relatives for plasma APOB and PCSK9 (very-low to undetectable in proband, approximately 50% decreased in sister and daughter) and LDL catabolic rate (256% and 88% increased in proband and daughter). Transient transfection in hepatocytes showed severely impaired processing and secretion of the double mutant which acted as a dominant negative over secretion of wild-type PCSK9.


CONCLUSIONS
These results show that heterozygous PCSK9 missense mutations may associate with profound hypobetalipoproteinemia and constitute the first direct evidence in human that decrease of plasma LDLC concentrations associated to PCSK9 LOF mutations are attributable to an increased clearance rate of LDL.
Cariou
Bertrand
B
INSERM, U915, Nantes F-44000, France.
Ouguerram
Khadija
K
Zaïr
Yassine
Y
Guerois
Raphael
R
Langhi
Cédric
C
Kourimate
Sanae
S
Benoit
Isabelle
I
Le May
Cédric
C
Gayet
Constance
C
Belabbas
Khaldia
K
Dufernez
Fabienne
F
Chétiveaux
Maud
M
Tarugi
Patrizia
P
Krempf
Michel
M
Benlian
Pascale
P
Costet
Philippe
P
D000328:Adult; D019943:Amino Acid Substitution; D001055:Apolipoproteins B / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D005799:Genes, Dominant; D022781:Hepatocytes / Q000201:enzymology; D006579:Heterozygote; D006801:Humans; D052476:Hypobetalipoproteinemia, Familial, Apolipoprotein B / Q000097:blood / Q000201:enzymology / Q000235:genetics; D006995:Hypobetalipoproteinemias / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000097:blood* / Q000172:deficiency / Q000235:genetics*; D014162:Transfection
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011994:Recombinant Proteins; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases