Chylomicronemia with low postheparin lipoprotein lipase levels in the setting of GPIHBP1 defects.
BACKGROUND
Recent studies in mice have established that an endothelial cell protein, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), is essential for the lipolytic processing of triglyceride-rich lipoproteins.


RESULTS
We report the discovery of a homozygous missense mutation in GPIHBP1 in a young boy with severe chylomicronemia. The mutation, p.C65Y, replaces a conserved cysteine in the GPIHBP1 lymphocyte antigen 6 domain with a tyrosine and is predicted to perturb protein structure by interfering with the formation of a disulfide bond. Studies with transfected Chinese hamster ovary cells showed that GPIHBP1-C65Y reaches the cell surface but has lost the ability to bind lipoprotein lipase (LPL). When the GPIHBP1-C65Y homozygote was given an intravenous bolus of heparin, only trace amounts of LPL entered the plasma. We also observed very low levels of LPL in the postheparin plasma of a subject with chylomicronemia who was homozygous for a different GPIHBP1 mutation (p.Q115P). When the GPIHBP1-Q115P homozygote was given a 6-hour infusion of heparin, a significant amount of LPL appeared in the plasma, resulting in a fall in the plasma triglyceride levels from 1780 to 120 mg/dL.


CONCLUSIONS
We identified a novel GPIHBP1 missense mutation (p.C65Y) associated with defective LPL binding in a young boy with severe chylomicronemia. We also show that homozygosity for the C65Y or Q115P mutations is associated with low levels of LPL in the postheparin plasma, demonstrating that GPIHBP1 is important for plasma triglyceride metabolism in humans.
Franssen
Remco
R
Department of Vascular Medicine, Academic Medical Center Amsterdam, The Netherlands.
Young
Stephen G
SG
Peelman
Frank
F
Hertecant
Jozef
J
Sierts
Jeroen A
JA
Schimmel
Alinda W M
AW
Bensadoun
André
A
Kastelein
John J P
JJ
Fong
Loren G
LG
Dallinga-Thie
Geesje M
GM
Beigneux
Anne P
AP
D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002675:Child, Preschool; D002914:Chylomicrons / Q000097:blood*; D006224:Cricetinae; D003412:Cricetulus; D005091:Exons; D006493:Heparin / Q000494:pharmacology; D006720:Homozygote; D006801:Humans; D008071:Lipoprotein Lipase / Q000097:blood* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D018110:Receptors, Lipoprotein; D014280:Triglycerides / Q000097:blood
D002352:Carrier Proteins; D002914:Chylomicrons; C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D014280:Triglycerides; D006493:Heparin; D008071:Lipoprotein Lipase