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Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches

PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids,...

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Main Authors: Himmelreich, Nastassja (Author) , Kikul, Frauke (Author) , Zdrazilova, Lucie (Author) , Honzik, Tomáš (Author) , Hecker, Andreas (Author) , Poschet, Gernot (Author) , Lüchtenborg, Christian (Author) , Brügger, Britta (Author) , Strahl, Sabine (Author) , Bürger, Friederike (Author) , Okun, Jürgen G. (Author) , Hansikova, Hana (Author) , Thiel, Christian (Author)
Format: Article (Journal)
Language:English
Published: 26 May 2023
In: Molecular genetics and metabolism
Year: 2023, Volume: 139, Issue: 3, Pages: 1-10
ISSN:1096-7206
DOI:10.1016/j.ymgme.2023.107610
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ymgme.2023.107610
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1096719223002408
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Author Notes:Nastassja Himmelreich, Frauke Kikul, Lucie Zdrazilova, Tomáš Honzik, Andreas Hecker, Gernot Poschet, Christian Lüchtenborg, Britta Brügger, Sabine Strahl, Friederike Bürger, Jürgen G. Okun, Hana Hansikova, Christian Thiel
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Summary:PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.
Item Description:Online verfügbar 16 May 2023, Version des Artikels 26 May 2023
Gesehen am 20.09.2023
Physical Description:Online Resource
ISSN:1096-7206
DOI:10.1016/j.ymgme.2023.107610

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