4638787
doi
10.5281/zenodo.4638787
oai:zenodo.org:4638787
Gerretsen, Eveline
Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Ashikov, Angel
Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
Vals, Mari-Anne
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Estonia
de Boer, Rinse
Molecular Cell Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
H. Revelo, Natalia
Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Arts, Richard
Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Baerenfaenger, Melissa
Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
Zijlstra, Fokje
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
Huijben, Karin
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
Raymond, Kimiyo
Department of Laboratory Medicine and Pathology, Mayo College of Medicine, Rochester, Minnesota, USA
Muru, Kai
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Estonia
Fjodorova, Olga
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia
Pajusalu, Sander
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Estonia
Õunap, Katrin
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Estonia
ter Beest, Martin
Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Lefeber, Dirk
Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
van den Bogaart, Geert
Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG, Groningen, Netherlands
Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
Linders, Peter
Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
doi:10.1101/2020.03.30.20044438
info:eu-repo/semantics/openAccess
Creative Commons Attribution 4.0 International
https://creativecommons.org/licenses/by/4.0/legalcode
syntaxin-5
ER-Golgi trafficking
glycosylation
secretory pathway
congenital disorders of glycosylation
<p>The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the <em>STX5</em> mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identified a novel human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients showed defective glycosylation, altered Golgi morphology as measured by electron microscopy and mislocalization of glycosyltransferases. Measurements of anterograde trafficking, based on biotin-synchronizable forms of Stx5 (the RUSH system), and of cognate binding SNAREs, based on Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. This is the first time a mutation in an alternative starting codon is linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking.</p>
N.H.R. is funded by a Long-Term Fellowship from the European Molecular Biology Organization (EMBO-LTF, ALTF 232-2016) and a Veni grant from the Netherlands Organization for Scientific Research (016.VENI.171.097). G.v.d.B. is funded by a Young Investigator Grant from the Human Frontier Science Program (HFSP; RGY0080/2018) and a Vidi grant from the Netherlands Organisation for Scientific Research (NWO-ALW VIDI 864.14.001). G.v.d.B has also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 862137). D.J.L. is funded by a Vidi grant (ZONMW VIDI 917.13.359), a ZONMW Medium Investment Grant (40-00506-98-9001) from the Netherlands Organisation for Scientific Research, and Erare grants EUROCDG2 and Euroglycanomics. K.Õ, M-A.V., S.P., and K.M. were supported by the Estonian Research Council grants GARLA8175, PUT355, PUTJD827 and PRG471.
Zenodo
2021-03-26
info:eu-repo/semantics/other
3816933
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public
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Is source of
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10.5281/zenodo.3816933
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