title: Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia.
abstract: We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia. LPL activity and mass in pre- and postheparin plasma were low, and LPL release into plasma after heparin injection was delayed. LPL activity and mass in adipose tissue biopsies appeared normal. [(35)S]Methionine incorporation studies on adipose tissue showed that newly synthesized LPL was normal in size and normally glycosylated. Breast milk from the affected female subjects contained normal to elevated LPL mass and activity levels. The milk had a lower than normal milk lipid content, and the fatty acid composition was compatible with the milk lipids being derived from de novo lipogenesis, rather than from the plasma lipoproteins. Given the delayed release of LPL into the plasma after heparin, we suspected that the chylomicronemia might be caused by mutations in GPIHBP1. Indeed, all three affected siblings were compound heterozygotes for missense mutations involving highly conserved cysteines in the Ly6 domain of GPIHBP1 (C65S and C68G). The mutant GPIHBP1 proteins reached the surface of transfected Chinese hamster ovary cells but were defective in their ability to bind LPL (as judged by both cell-based and cell-free LPL binding assays). Thus, the conserved cysteines in the Ly6 domain are crucial for GPIHBP1 function.
authors.affiliation: Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden. gunilla.olivecrona@medbio.umu.se
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
authors.forename: Ewa
authors.initials: E
authors.lastname: Ehrenborg
authors.forename: Henrik
authors.initials: H
authors.lastname: Semb
authors.forename: Elena
authors.initials: E
authors.lastname: Makoveichuk
authors.forename: Anna
authors.initials: A
authors.lastname: Lindberg
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Peter
authors.initials: P
authors.lastname: Gin
authors.forename: Brandon S J
authors.initials: BS
authors.lastname: Davies
authors.forename: Michael M
authors.initials: MM
authors.lastname: Weinstein
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Anne P
authors.initials: AP
authors.lastname: Beigneux
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Thomas
authors.initials: T
authors.lastname: Olivecrona
authors.forename: Olle
authors.initials: O
authors.lastname: Hernell
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D053304:Apolipoprotein C-II / Q000172:deficiency; D001483:Base Sequence; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D002914:Chylomicrons / Q000378:metabolism*; D017124:Conserved Sequence; D006224:Cricetinae; D003412:Cricetulus; D003545:Cysteine; D005260:Female; D005786:Gene Expression Regulation; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D052439:Lipid Metabolism Disorders / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008895:Milk, Human / Q000201:enzymology; D009154:Mutation; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D018110:Receptors, Lipoprotein; D035781:Siblings; D014162:Transfection
chemical_list: D053304:Apolipoprotein C-II; D002352:Carrier Proteins; D002914:Chylomicrons; C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D006493:Heparin; C548261:LPL protein, human; D008071:Lipoprotein Lipase; D003545:Cysteine