Titre :

Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation Defects

Auteur(s) :

Morelle, Willy [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Potelle, Sven [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Witters, Peter [Auteur]
University Hospitals Leuven [Leuven]
Wong, Sunnie [Auteur]
Tulane University
Climer, Leslie [Auteur]
University of Arkansas for Medical Sciences [UAMS]
Lupashin, Vladimir [Auteur]
University of Arkansas for Medical Sciences [UAMS]
Matthijs, Gert [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Gadomski, Therese [Auteur]
Tulane University
Jaeken, Jaak [Auteur]
University Hospitals Leuven [Leuven]
Cassiman, David [Auteur]
University Hospitals Leuven [Leuven]
Morava, Eva [Auteur]
Tulane University
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Titre de la revue :

The Journal of clinical endocrinology and metabolism

Nom court de la revue :

J. Clin. Endocrinol. Metab.

Numéro :

102

Pagination :

1375-1386

Date de publication :

2017-04-01

ISSN :

1945-7197

Mot(s)-clé(s) en anglais :

Humans
Male
Treatment Outcome
Glycosylation
Congenital Disorders of Glycosylation
HEK293 Cells
Fibroblasts
Adult
Membrane Protein
Mutation
Galactose
Child
Dietary Supplements

Discipline(s) HAL :

Chimie/Chimie théorique et/ou physique

Résumé en anglais : [en]

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 ...
Lire la suite >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: We analyzed N-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.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Projet Européen :

ERA-NET rare disease research implementing IRDiRC objectives

Projet ANR :

Décryptage des patients CDG (Congenital Disorders of Glyvosylation) déficients en TMEM165 - de la compréhension des mécanismes moléculaires à une thérapie

Établissement(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Équipe(s) de recherche :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Date de dépôt :

2020-02-12T15:11:56Z
2021-07-13T07:04:51Z