Galactose supplementation in patients with TMEM165-CDG rescues the glycosylation defects

Willy Morelle, Sven Potelle, Peter Witters, Sunnie Wong, Leslie Climer, Vladimir Lupashin, Gert Matthijs, Therese Gadomski, Jaak Jaeken, David Cassiman, Eva Morava-Kozicz, François Foulquier

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Context: TMEM165 deficiency is a severe multisystem disease that manifests with metabolic, endocrine, and skeletal involvement. It leads to one type of congenital disorders of glycosylation (CDG), a rapidly growing group of inherited diseases in which the glycosylation process is altered. Patients have decreased galactosylation by serum glycan analysis. There are >100 CDGs, but only specific types are treatable. Objective: Galactose has been shown to be beneficial in other CDG types with abnormal galactosylation. The aim of this study was to characterize the effects of galactose supplementation on Golgi glycosylation in TMEM165-depleted HEK293 cells, as well as in 2 patients with TMEM165-CDG and in their cultured skin fibroblast cells. Design and Setting: Glycosylation was assessed by mass spectrometry, western blot analysis, and transferrin isoelectrofocusing. Patients and Interventions: Both unrelated patients with TMEM165-CDG with the same deep intronic homozygous mutation (c.792+182G>A) were allocated to receive D-galactose in a daily dose of 1 g/kg. Results:WeanalyzedN-linked glycans and glycolipids in knockout TMEM165 HEK293 cells, revealing severe hypogalactosylation and GalNAc transfer defects. Although these defects were completely corrected by the addition of Mn2+, we demonstrated that the observed N-glycosylation defect could also be overcome by galactose supplementation. We then demonstrated that oral galactose supplementation in patients with TMEM165-deficient CDG improved biochemical and clinical parameters, including a substantial increase in the negatively charged transferrin isoforms, and a decrease in hypogalactosylated total N-glycan structures, endocrine function, and coagulation parameters. Conclusion: To our knowledge, this is the first description of abnormal glycosylation of lipids in the TMEM165 defect and the first report of successful dietary treatment in TMEM165 deficiency. We recommend the use of oral D-galactose therapy in TMEM165-CDG.

Original languageEnglish (US)
Pages (from-to)1375-1386
Number of pages12
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number4
DOIs
StatePublished - Apr 1 2017
Externally publishedYes

Fingerprint

Congenital Disorders of Glycosylation
Glycosylation
Galactose
Defects
Polysaccharides
HEK293 Cells
Transferrin
Glycolipids
Mass Spectrometry
Protein Isoforms
Fibroblasts
Western Blotting
Lipids
Skin
Mutation
Coagulation
Therapeutics
Serum
Mass spectrometry

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Morelle, W., Potelle, S., Witters, P., Wong, S., Climer, L., Lupashin, V., ... Foulquier, F. (2017). Galactose supplementation in patients with TMEM165-CDG rescues the glycosylation defects. Journal of Clinical Endocrinology and Metabolism, 102(4), 1375-1386. https://doi.org/10.1210/jc.2016-3443

Galactose supplementation in patients with TMEM165-CDG rescues the glycosylation defects. / Morelle, Willy; Potelle, Sven; Witters, Peter; Wong, Sunnie; Climer, Leslie; Lupashin, Vladimir; Matthijs, Gert; Gadomski, Therese; Jaeken, Jaak; Cassiman, David; Morava-Kozicz, Eva; Foulquier, François.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 102, No. 4, 01.04.2017, p. 1375-1386.

Research output: Contribution to journalArticle

Morelle, W, Potelle, S, Witters, P, Wong, S, Climer, L, Lupashin, V, Matthijs, G, Gadomski, T, Jaeken, J, Cassiman, D, Morava-Kozicz, E & Foulquier, F 2017, 'Galactose supplementation in patients with TMEM165-CDG rescues the glycosylation defects', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 4, pp. 1375-1386. https://doi.org/10.1210/jc.2016-3443
Morelle, Willy ; Potelle, Sven ; Witters, Peter ; Wong, Sunnie ; Climer, Leslie ; Lupashin, Vladimir ; Matthijs, Gert ; Gadomski, Therese ; Jaeken, Jaak ; Cassiman, David ; Morava-Kozicz, Eva ; Foulquier, François. / Galactose supplementation in patients with TMEM165-CDG rescues the glycosylation defects. In: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, No. 4. pp. 1375-1386.
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AU - Climer, Leslie

AU - Lupashin, Vladimir

AU - Matthijs, Gert

AU - Gadomski, Therese

AU - Jaeken, Jaak

AU - Cassiman, David

AU - Morava-Kozicz, Eva

AU - Foulquier, François

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