title: GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia.
abstract: BACKGROUND
  GPIHBP1 is a new endothelial binding site for lipoprotein lipase (LPL), the key enzyme for intravascular lipolysis of triglyceride-rich lipoproteins (TGRL). We have identified two new missense mutations of the GPIHBP1 gene, C89F and G175R, by systematic sequencing in a cohort of 376 hyperchylomicronemic patients without mutations on the LPL, APOC2, or APOA5 gene.
  
  
  OBJECTIVE
  Phenotypic expression and functional consequences of these two mutations were studied.
  
  
  METHODS
  We performed clinical and genotypic studies of probands and their families. GPIHBP1 functional alterations were studied in CHO pgsA-745 transfected cells.
  
  
  RESULTS
  Probands are an adult with a homozygous G175R mutation and a child with a hemizygous C89F neomutation and a deletion of the second allele. C89F mutation was associated with a C14F signal peptide polymorphism on the same haplotype. Both patients had resistant hyperchylomicronemia, low LPL activity, and history of acute pancreatitis. In CHO pgsA-745 cells, both G175R and C14F variants reduce the expression of GPIHBP1 at the cell surface. C89F mutation is responsible for a drastic LPL-binding defect to GPIHBP1. C14F may further potentiate C89F effect.
  
  
  CONCLUSIONS
  The emergence of hyperchylomicronemia in the generation after a neomutation further establishes a critical role for GPIHBP1 in TGRL physiopathology in humans. Our results highlight the crucial role of C65-C89 disulfide bond in LPL binding by GPIHBP1 Ly6 domain. Furthermore, we first report a mutation of the hydrophobic C-terminal domain that impairs GPIHBP1 membrane targeting.
authors.affiliation: Hôpital Louis Pradel, Fédération d'Endocrinologie, Bron Cedex, France. sybil.charriere@chu-lyon.fr
authors.forename: Sybil
authors.initials: S
authors.lastname: Charrière
authors.forename: Noël
authors.initials: N
authors.lastname: Peretti
authors.forename: Sophie
authors.initials: S
authors.lastname: Bernard
authors.forename: Mathilde
authors.initials: M
authors.lastname: Di Filippo
authors.forename: Agnès
authors.initials: A
authors.lastname: Sassolas
authors.forename: Micheline
authors.initials: M
authors.lastname: Merlin
authors.forename: Mireille
authors.initials: M
authors.lastname: Delay
authors.forename: Cyrille
authors.initials: C
authors.lastname: Debard
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.forename: Alain
authors.initials: A
authors.lastname: Lachaux
authors.forename: Philippe
authors.initials: P
authors.lastname: Moulin
authors.forename: Christophe
authors.initials: C
authors.lastname: Marçais
mesh_terms: D000328:Adult; D000818:Animals; D000072040:Apolipoprotein A-V; D053304:Apolipoprotein C-II / Q000235:genetics / Q000378:metabolism; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics*; D002914:Chylomicrons / Q000097:blood* / Q000235:genetics*; D015331:Cohort Studies; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000235:genetics; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood* / Q000235:genetics*; D007223:Infant; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D009154:Mutation / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D010195:Pancreatitis / Q000150:complications / Q000235:genetics; D010375:Pedigree; D018110:Receptors, Lipoprotein
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D053304:Apolipoprotein C-II; D001054:Apolipoproteins A; D002352:Carrier Proteins; D002914:Chylomicrons; C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D004247:DNA; D008071:Lipoprotein Lipase