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A spoonful of L-fucose: an efficient therapy for GFUS-CDG, a new glycosylation disorder

Congenital disorders of glycosylation are a genetically and phenotypically heterogeneous family of diseases affecting the co- and posttranslational modification of proteins. Using exome sequencing, we detected biallelic variants in GFUS (NM_003313.4) c.[632G>A];[659C>T] (p.[Gly211Glu];[Ser220L...

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Hauptverfasser: Feichtinger, René (Verfasst von) , Hüllen, Andreas (Verfasst von) , Koller, Andreas (Verfasst von) , Kotzot, Dieter (Verfasst von) , Grote, Valerian (Verfasst von) , Rapp, Erdmann (Verfasst von) , Hofbauer, Peter (Verfasst von) , Brugger, Karin (Verfasst von) , Thiel, Christian (Verfasst von) , Mayr, Johannes A. (Verfasst von) , Wortmann, Saskia B. (Verfasst von)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 1 September 2021
In: EMBO molecular medicine
Year: 2021, Jahrgang: 13, Heft: 9, Pages: 1-15
ISSN:1757-4684
DOI:10.15252/emmm.202114332
Online-Zugang:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.15252/emmm.202114332
Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.15252/emmm.202114332
Volltext
Verfasserangaben:René G. Feichtinger, Andreas Hüllen, Andreas Koller, Dieter Kotzot, Valerian Grote, Erdmann Rapp, Peter Hofbauer, Karin Brugger, Christian Thiel, Johannes A. Mayr & Saskia B. Wortmann
Beschreibung
Zusammenfassung:Congenital disorders of glycosylation are a genetically and phenotypically heterogeneous family of diseases affecting the co- and posttranslational modification of proteins. Using exome sequencing, we detected biallelic variants in GFUS (NM_003313.4) c.[632G>A];[659C>T] (p.[Gly211Glu];[Ser220Leu]) in a patient presenting with global developmental delay, mild coarse facial features and faltering growth. GFUS encodes GDP-L-fucose synthase, the terminal enzyme in de novo synthesis of GDP-L-fucose, required for fucosylation of N- and O-glycans. We found reduced GFUS protein and decreased GDP-L-fucose levels leading to a general hypofucosylation determined in patient's glycoproteins in serum, leukocytes, thrombocytes and fibroblasts. Complementation of patient fibroblasts with wild-type GFUS cDNA restored fucosylation. Making use of the GDP-L-fucose salvage pathway, oral fucose supplementation normalized fucosylation of proteins within 4 weeks as measured in serum and leukocytes. During the follow-up of 19 months, a moderate improvement of growth was seen, as well as a clear improvement of cognitive skills as measured by the Kaufmann ABC and the Nijmegen Pediatric CDG Rating Scale. In conclusion, GFUS-CDG is a new glycosylation disorder for which oral L-fucose supplementation is promising.
Beschreibung:Gesehen am 07.10.2021
Beschreibung:Online Resource
ISSN:1757-4684
DOI:10.15252/emmm.202114332

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