Cover Image

A novel missense variant in ultrarare SLC35A1-CDG alters cellular glycosylation, lipid, and energy metabolism without affecting CDG serum markers

SLC35A1-CDG is a very rare type of congenital disorders of glycosylation (CDG) with only five cases known to date. Here, we review the literature and present new data from a sixth patient carrying the uncharacterized variant c.133A>G; p.Thr45Ala in the SLC35A1 gene. In addition to known clinical...

Full description

Saved in:
Bibliographic Details
Main Authors: Falkenstein, Kristina (Author) , Hoeren, Lukas (Author) , Kikul, Frauke (Author) , Poschet, Gernot (Author) , Lüchtenborg, Christian (Author) , Brecht, Ines B. (Author) , Falb, Ruth (Author) , Gauck, Darja (Author) , Haack, Tobias (Author) , Hecker, Andreas (Author) , Himmelreich, Nastassja (Author) , Okun, Jürgen G. (Author) , Brügger, Britta (Author) , Thiel, Christian (Author)
Format: Article (Journal)
Language:English
Published: Jan 2025
In: Human mutation
Year: 2025, Issue: 1, Pages: 1-14
ISSN:1098-1004
DOI:10.1155/humu/6290620
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1155/humu/6290620
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1155/humu/6290620
Get full text
Author Notes:Kristina Falkenstein, Lukas Hoeren, Frauke Kikul, Gernot Poschet, Christian Lüchtenborg, Ines B. Brecht, Ruth Falb, Darja Gauck, Tobias Haack, Andreas Hecker, Nastassja Himmelreich, Jürgen G. Okun, Britta Brügger, and Christian Thiel
Description
Summary:SLC35A1-CDG is a very rare type of congenital disorders of glycosylation (CDG) with only five cases known to date. Here, we review the literature and present new data from a sixth patient carrying the uncharacterized variant c.133A>G; p.Thr45Ala in the SLC35A1 gene. In addition to known clinical symptoms of SLC35A1-CDG, the patient presents with failure to thrive, short stature, café-au-lait spot, and preauricular ear tag. Even though examination of CDG markers transferrin (Tf), alpha-1-antitrypsin (A1AT), and apolipoprotein CIII (ApoCIII) revealed no abnormalities in serum, the patient’s fibroblasts showed significant alterations of protein expression or glycosylation of ICAM1, GP130, and TGN46 as well as differences in staining signals of lectins MAL-I, RCAI, and SNA and deviations in LC-MS analysis of total cellular N-glycans. Transfection of CRISPR/Cas9 generated SLC35A1 HEK293 knockout cells with either wild-type SLC35A1 or the c.133A>G variant restored the cellular CMP-Neu5Ac to wild-type levels, making a direct effect of p.Thr45Ala on the function of the transporter unlikely. Instead, our results imply that the residual transporter activity of 65% is caused by a decreased stability of the mutated SLC35A1 protein. Since O-GlcNAcylation was affected as well, energy and lipid homeostasis were analyzed and found to be significantly altered. Notably, proliferation and glycosylation of the SLC35A1-deficient patient fibroblasts were enhanced by supplementation of the cell culture medium with 10 mM GlcNAc.
Item Description:Online veröffentlicht: 26. Juni 2025
Gesehen am 03.11.2025
Physical Description:Online Resource
ISSN:1098-1004
DOI:10.1155/humu/6290620

Similar Items