Deletion of GPIHBP1 causing severe chylomicronemia

Abstract

Lipoprotein lipase (LPL) is a hydrolase that cleaves circulating triglycerides to release fatty acids to the surrounding tissues. The enzyme is synthesized in parenchymal cells and is transported to its site of action on the capillary endothelium by glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Inactivating mutations in LPL; in its cofactor, apolipoprotein (Apo) C2; or in GPIHBP1 cause severe hypertriglyceridemia. Here we describe an individual with complete deficiency of GPIHBP1. The proband was an Asian Indian boy who had severe chylomicronemia at 2 months of age. Array-based copy-number analysis of his genomic DNA revealed homozygosity for a 17.5-kb deletion that included GPIHBP1. A 44-year-old aunt with a history of hypertriglyceridemia and pancreatitis was also homozygous for the deletion. A bolus of intravenously administered heparin caused a rapid increase in circulating LPL and decreased plasma triglyceride levels in control individuals but not in two GPIHBP1-deficient patients. Thus, short-term treatment with heparin failed to attenuate the hypertriglyceridemia in patients with GPIHBP1 deficiency. The increasing resolution of copy number microarrays and their widespread adoption for routine cytogenetic analysis is likely to reveal a greater role for submicroscopic deletions in Mendelian conditions. We describe the first neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-011-9406-5) contains supplementary material, which is available to authorized users.

An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

“…Fab′ fragments were prepared with immobilized papain and Fc fragments removed with Protein LU domain is primarily responsible for high-affinity binding of LPL, while the acidic domain augments the interaction and promotes an initial interaction complex between LPL and GPIHBP1 (6,11). A variety of missense mutations in GPIHBP1's LU domain have been identified in patients with chylomicronemia (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and all of those abolish the ability of GPIHBP1 to bind LPL (6). Most of these mutations interfere with the formation of disulfide bonds in the LU domain, leading to disulfide-linked dimers and multimers (23).…”

Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1

“…This transport is carried out by GPIHBP1, which binds LPL secreted by parenchymal cells and transcytotically transports it to the capillary lumen (9 -11). In GPIHBP1-deficient mice, LPL accumulates in the interstitial space and is absent from the capillary lumen, resulting in a dramatic reduction in triglyceride processing and severely elevated plasma triglyceride levels (9,10,(12)(13)(14)(15)(16)(17)(18).…”

Novel Combined GPIHBP1 Mutations in a Patient with Hypertriglyceridemia Associated with CAD

“…There have been several reports demonstrating mutations in GPIHBP1 proteins in human patients [28][29][30][31][32][33] . The universal clinical feature is chylomicronemia; however, other complications, such as lipemia (WHHL) rabbits exhibits proatherogenic effects 20) .…”

“…The C14F mutation is recognized to be an SNP; however, the C68R mutation itself and the combined mutations are novel, although other amino acid alterations at C68 have been reported 28,29,31) . C68 is one of 10 highly conserved cysteine residues in the Ly6 domain of GPIHBP1 and is predicted to form a three-fingered structure.…”