Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
Creators
- 1. Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- 2. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
- 3. Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Estonia
- 4. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
- 5. Department of Laboratory Medicine and Pathology, Mayo College of Medicine, Rochester, Minnesota, USA
- 6. Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia
- 7. Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG, Groningen, Netherlands
Description
The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 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. Whereas Golgi morphology was unaltered, primary human dermal fibroblasts isolated from these patients showed defective glycosylation 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.
- The organisation of the data is found in Linders_DescriptionOfData.xlsx in the root directory
Notes
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Additional details
Related works
- Is source of
- Preprint: 10.1101/2020.03.30.20044438 (DOI)