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

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We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia. Lipoprotein lipase (LPL) activity and mass in pre- and post-heparin 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 CHO 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.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
compound heterozygote
lipoprotein lipase
milk lipids
mammary gland
glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1
endothelial cells

Ehrenborg, EwaKarolinska Institutet (författare)
Semb, HenrikUmeå universitet,Fysiologisk kemi (författare)
Makoveichuk, ElenaUmeå universitet,Fysiologisk kemi(Swepub:umu)elma0002 (författare)
Lindberg, AnnaUmeå universitet,Fysiologisk kemi (författare)
Hayden, Michael R (författare)
Gin, Peter (författare)
Davies, Brandon S J (författare)
Weinstein, Michael M (författare)
Fong, Loren G (författare)
Beigneux, Anne P (författare)
Young, Stephen G (författare)
Olivecrona, ThomasUmeå universitet,Fysiologisk kemi(Swepub:umu)thol0003 (författare)
Hernell, OlleUmeå universitet,Pediatrik(Swepub:umu)olhe0002 (författare)
Umeå universitetFysiologisk kemi (creator_code:org_t)

Ingår i:Journal of Lipid ResearchNew York : Rockefeller U.P.51:6, s. 1535-15450022-22751539-7262

Av författaren/redakt...: Olivecrona, Guni ...; Ehrenborg, Ewa; Semb, Henrik; Makoveichuk, Ele ...; Lindberg, Anna; Hayden, Michael ...; visa fler...; Gin, Peter; Davies, Brandon ...; Weinstein, Micha ...; Fong, Loren G; Beigneux, Anne P; Young, Stephen G; Olivecrona, Thom ...; Hernell, Olle; visa färre...

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