title: Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase.
abstract: OBJECTIVE
  GPIHBP1 is an endothelial cell protein that binds lipoprotein lipase (LPL) and chylomicrons. Because GPIHBP1 deficiency causes chylomicronemia in mice, we sought to determine whether some cases of chylomicronemia in humans could be attributable to defective GPIHBP1 proteins.
  
  
  RESULTS
  Patients with severe hypertriglyceridemia (n=60, with plasma triglycerides above the 95th percentile for age and gender) were screened for mutations in GPIHBP1. A homozygous GPIHBP1 mutation (c.344A>C) that changed a highly conserved glutamine at residue 115 to a proline (p.Q115P) was identified in a 33-year-old male with lifelong chylomicronemia. The patient had failure-to-thrive as a child but had no history of pancreatitis. He had no mutations in LPL, APOA5, or APOC2. The Q115P substitution did not affect the ability of GPIHBP1 to reach the cell surface. However, unlike wild-type GPIHBP1, GPIHBP1-Q115P lacked the ability to bind LPL or chylomicrons (d < 1.006 g/mL lipoproteins from Gpihbp1(-/-) mice). Mouse GPIHBP1 with the corresponding mutation (Q114P) also could not bind LPL.
  
  
  CONCLUSIONS
  A homozygous missense mutation in GPIHBP1 (Q115P) was identified in a patient with chylomicronemia. The mutation eliminated the ability of GPIHBP1 to bind LPL and chylomicrons, strongly suggesting that it caused the patient's chylomicronemia.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. abeigneux@mednet.ucla.edu
authors.forename: Anne P
authors.initials: AP
authors.lastname: Beigneux
authors.forename: Remco
authors.initials: R
authors.lastname: Franssen
authors.forename: André
authors.initials: A
authors.lastname: Bensadoun
authors.forename: Peter
authors.initials: P
authors.lastname: Gin
authors.forename: Kristan
authors.initials: K
authors.lastname: Melford
authors.forename: Jorge
authors.initials: J
authors.lastname: Peter
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Walzem
authors.forename: Michael M
authors.initials: MM
authors.lastname: Weinstein
authors.forename: Brandon S J
authors.initials: BS
authors.lastname: Davies
authors.forename: Jan A
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002914:Chylomicrons / Q000235:genetics* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006720:Homozygote; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D015228:Hypertriglyceridemia / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D018110:Receptors, Lipoprotein / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D002914:Chylomicrons; C472779:GPI-HBP1 protein, mouse; C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D008071:Lipoprotein Lipase