Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia

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 nor...

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Bibliographic Details
Published in:Journal of Lipid Research
Main Authors: Gunilla Olivecrona, Ewa Ehrenborg, Henrik Semb, Elena Makoveichuk, Anna Lindberg, Michael R. Hayden, Peter Gin, Brandon S.J. Davies, Michael M. Weinstein, Loren G. Fong, Anne P. Beigneux, Stephen G. Young, Thomas Olivecrona, Olle Hernell
Format: Article in Journal/Newspaper
Language:English
Published: Elsevier 2010
Subjects:
compound heterozygote
lipoprotein lipase
milk lipids
mammary gland
glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1
endothelial cells
Biochemistry
QD415-436
Northern Sweden
Online Access:https://doi.org/10.1194/jlr.M002717
https://doaj.org/article/226263a59d074257b997e47bc4243b1a
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Summary: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. [35S]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.

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