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

Gunilla Olivecrona¹^,*, Ewa Ehrenborg^,, Henrik Semb²^,*, Elena Makoveichuk^*, Anna Lindberg³^,*, Michael R. Hayden, Peter Gin^**, Brandon S. J. Davies^**, Michael M. Weinstein^**, Loren G. Fong^**, Anne P. Beigneux^**, Stephen G. Young^**, Thomas Olivecrona^** and Olle Hernell

^* Department of Medical Biosciences/Physiological Chemistry
Department of Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden
Department of Medicine, Karolinska Institute, Stockholm, Sweden
Departments of Medical Genetics and Medicine, University of British Columbia, Vancouver, Canada
^** Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA

¹ To whom correspondence should be addressed. e-mail: gunilla.olivecrona{at}medbio.umu.se

We investigated a family from northern Sweden in which threeof four siblings have congenital chylomicronemia. LPL activityand mass in pre- and postheparin plasma were low, and LPL releaseinto plasma after heparin injection was delayed. LPL activityand mass in adipose tissue biopsies appeared normal. [³⁵S]Methionineincorporation studies on adipose tissue showed that newly synthesizedLPL was normal in size and normally glycosylated. Breast milkfrom the affected female subjects contained normal to elevatedLPL mass and activity levels. The milk had a lower than normalmilk lipid content, and the fatty acid composition was compatiblewith the milk lipids being derived from de novo lipogenesis,rather than from the plasma lipoproteins. Given the delayedrelease of LPL into the plasma after heparin, we suspected thatthe chylomicronemia might be caused by mutations in GPIHBP1.Indeed, all three affected siblings were compound heterozygotesfor missense mutations involving highly conserved cysteinesin the Ly6 domain of GPIHBP1 (C65S and C68G). The mutant GPIHBP1proteins reached the surface of transfected Chinese hamsterovary 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 crucialfor GPIHBP1 function.

Supplementary key words compound heterozygote • lipoprotein lipase • milk lipids • mammary gland • glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 • endothelial cells

Abbreviations: CHO, Chinese hamster ovary; GPIHBP1, glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1; PIPLC, phosphatidylinositol-specific phospholipase C

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

Patient-Oriented and Epidemiological Research

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