Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain.
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.
From the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok 10330, Thailand.
Wanee
W
Plengpanich
the Departments of Medicine and Human Genetics, UCLA, Los Angeles, California 90095.
Stephen G
SG
Young
From the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok 10330, Thailand, wkhovid@gmail.com.
Weerapan
W
Khovidhunkit
the Division of Nutritional Science, Cornell University, Ithaca, New York 14853.
André
A
Bensadoun
From the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok 10330, Thailand.
Hirankorn
H
Karnman
the Finsen Laboratory and Biotech Research and Innovation Center, Rigshospitalet, DK-2200 Copenhagen, Denmark.
Michael
M
Ploug
the Finsen Laboratory and Biotech Research and Innovation Center, Rigshospitalet, DK-2200 Copenhagen, Denmark.
Henrik
H
Gårdsvoll
the Departments of Medicine and.
Calvin S
CS
Leung
the Departments of Medicine and.
Oludotun
O
Adeyo
the Department of Medical Biosciences and Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden, and.
Mikael
M
Larsson
From the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok 10330, Thailand.
Suwanna
S
Muanpetch
From the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok 10330, Thailand.
Supannika
S
Charoen
the Departments of Medicine and.
Loren G
LG
Fong
the Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok 10400, Thailand.
Sathit
S
Niramitmahapanya
the Departments of Medicine and abeigneux@mednet.ucla.edu.
Anne P
AP
Beigneux
D000328:Adult; D019943:Amino Acid Substitution; D002460:Cell Line; D006720:Homozygote; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020125:Mutation, Missense; D011485:Protein Binding / Q000235:genetics; D055503:Protein Multimerization / Q000235:genetics*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism
C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D008071:Lipoprotein Lipase
Disulfide; Genetics; Hypertriglyceridemia; Lipolysis; Lipoprotein Lipase; Mutation; Protein Folding; Protein-Protein Interaction