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J Biol Chem. 2014 Jul 11;289(28):19491-9. doi: 10.1074/jbc.M114.558528. Epub 2014 May 20.

Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain.

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From the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok 10330, Thailand.
the Departments of Medicine and Human Genetics, UCLA, Los Angeles, California 90095.
From the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok 10330, Thailand,
the Division of Nutritional Science, Cornell University, Ithaca, New York 14853.
the Finsen Laboratory and Biotech Research and Innovation Center, Rigshospitalet, DK-2200 Copenhagen, Denmark.
the Departments of Medicine and.
the Department of Medical Biosciences and Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden, and.
the Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok 10400, Thailand.
the Departments of Medicine and


GPIHBP1, a glycosylphosphatidylinositol-anchored glycoprotein of microvascular endothelial cells, binds lipoprotein lipase (LPL) within the interstitial spaces and transports it across endothelial cells to the capillary lumen. The ability of GPIHBP1 to bind LPL depends on the Ly6 domain, a three-fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in the GPIHBP1 Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were homozygous for the same mutation. All three homozygotes had very low levels of LPL in the preheparin plasma. We suspected that the extra cysteine in GPIHBP1-S107C might prevent the trafficking of the protein to the cell surface, but this was not the case. However, nearly all of the GPIHBP1-S107C on the cell surface was in the form of disulfide-linked dimers and multimers, whereas wild-type GPIHBP1 was predominantly monomeric. An insect cell GPIHBP1 expression system confirmed the propensity of GPIHBP1-S107C to form disulfide-linked dimers and to form multimers. Functional studies showed that only GPIHBP1 monomers bind LPL. In keeping with that finding, there was no binding of LPL to GPIHBP1-S107C in either cell-based or cell-free binding assays. We conclude that an extra cysteine in the GPIHBP1 Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia.


Disulfide; Genetics; Hypertriglyceridemia; Lipolysis; Lipoprotein Lipase; Mutation; Protein Folding; Protein-Protein Interaction

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