Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation Defects
Autor: | Gert Matthijs, Eva Morava, Leslie K. Climer, Sunnie Wong, Willy Morelle, Vladimir Lupashin, Peter Witters, David Cassiman, Sven Potelle, Therese Gadomski, François Foulquier, Jaak Jaeken |
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Přispěvatelé: | Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), University Hospitals Leuven [Leuven], Tulane University, University of Arkansas for Medical Sciences (UAMS), Center for Human Genetics, University of Leuven School of Medicine, SCHOOL of MEDICINE [Louvain], Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), ANR-15-CE14-0001,SOLV_CDG,Décryptage des patients CDG (Congenital Disorders of Glyvosylation) déficients en TMEM165 - de la compréhension des mécanismes moléculaires à une thérapie(2015), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS) |
Rok vydání: | 2017 |
Předmět: |
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0301 basic medicine Glycosylation Endocrinology Diabetes and Metabolism Clinical Biochemistry Biochemistry Antiporters chemistry.chemical_compound Congenital Disorders of Glycosylation Endocrinology Child Cation Transport Proteins Membrane Protein chemistry.chemical_classification biology medicine.diagnostic_test 3. Good health [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry Treatment Outcome lipids (amino acids peptides and proteins) Adult congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Glycan Context (language use) Abnormal glycosylation 03 medical and health sciences Glycolipid Western blot Internal medicine medicine Humans Clinical Research Articles business.industry Biochemistry (medical) Membrane Proteins Galactose Fibroblasts carbohydrates (lipids) HEK293 Cells 030104 developmental biology chemistry Transferrin Mutation Dietary Supplements biology.protein business |
Zdroj: | The Journal of clinical endocrinology & metabolism The Journal of clinical endocrinology & metabolism, 2017, The Journal of clinical endocrinology and metabolism, 102 (4), pp.1375-1386. ⟨10.1210/jc.2016-3443⟩ |
ISSN: | 1945-7197 0021-972X |
Popis: | International audience; 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. |
Databáze: | OpenAIRE |
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