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. 2020 May;43(3):611-617.
doi: 10.1002/jimd.12200. Epub 2019 Dec 29.

Reduced CETP glycosylation and activity in patients with homozygous B4GALT1 mutations

Marjolein A W van den Boogert  1 , Cleo L Crunelle  2 , Lubna Ali  3 , Lars E Larsen  3 , Sacha D Kuil  4 , Johannes H M Levels  3 , Alinda W M Schimmel  3 , Vassiliki Konstantopoulou  5 , Maryse Guerin  6 , Jan Albert Kuivenhoven  7 , Geesje M Dallinga-Thie  3 , Erik S G Stroes  1 , Dirk J Lefeber  4   8 , Adriaan G Holleboom  1
Affiliations

Reduced CETP glycosylation and activity in patients with homozygous B4GALT1 mutations

Marjolein A W van den Boogert et al. J Inherit Metab Dis. 2020 May.

Abstract

The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1-CDG, caused by a mutation in B4GALT1 with defective N-linked glycosylation. We studied plasma lipids, cholesteryl ester transfer protein (CETP) glyco-isoforms with isoelectric focusing followed by a western blot and CETP activity in three known B4GALT1-CDG patients and compared them with 11 age- and gender-matched, healthy controls. B4GALT1-CDG patients have significantly lowered non-high density lipoprotein cholesterol (HDL-c) and total cholesterol to HDL-c ratio compared with controls and larger HDL particles. Plasma CETP was hypoglycosylated and less active in B4GALT1-CDG patients compared to matched controls. Our study provides insight into the role of protein glycosylation in human lipoprotein homeostasis. The hypogalactosylated, hypo-active CETP found in patients with B4GALT1-CDG indicates a role of protein galactosylation in regulating plasma HDL and LDL. Patients with B4GALT1-CDG have large HDL particles probably due to hypogalactosylated, hypo-active CETP.

Keywords: B4GALT1; CDG; CETP; HDL; LDL; glycosylation; lipids.

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Conflict of interest statement

The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1
Hypoglycosylated hypo‐active CETP in B4GALT1‐CDG patients. A, Pooled FPLC trace of child controls (top panel), representative traces of patients B1 and B2 (middle panel) and a CETP deficient patient (bottom panel). The vertical line illustrates the clear HDL peak shift to the left in B4GALT1 and CETP patients, indicating the HDL size increment. B, Representative blot of CETP isoelectric focusing of a control (Ctrl1), a control treated with neuraminidase (Ctrl + NA), patient B2, patient B3, and a different control (Ctrl2). C, CETP activity in B4GALT1 patients vs age‐ and gender‐matched controls. CETP, cholesteryl ester transfer protein; FPLC, fast protein liquid chromatography
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