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

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

doi:10.1194/jlr.m002717

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.

Highlights

We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia
We show that all three affected siblings were compound heterozygotes for two mutant glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) alleles, each harboring a missense mutation involving a highly conserved Cys within the Ly6 domain of GPIHBP1
We explored the biochemical basis for chylomicronemia in three siblings from northern Sweden

Summary

Introduction

We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia. LPL activity and mass in adipose tissue biopsies appeared normal. Given the delayed release of LPL into the plasma after heparin, we suspected that the chylomicronemia might be caused by mutations in GPIHBP1. Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia. LPL is synthesized primarily in parenchymal cells in skeletal muscle, heart, and adipose tissue [1, 2] but finds its way into the lumen of capillaries, where it participates in the processing of the plasma lipoproteins. Its function within the milk is unknown, but there is little doubt that LPL-mediated processing of lipoproteins within the capillaries of the mammary gland is important for providing the lipid nutrients to produce milk fat.

Methods

Results

Conclusion