Congenital disorder of glycosylation caused by starting site specific variant in syntaxin-5

Peter Linders, Eveline Gerretsen, Angel Ashikov, Mari-Anne Vals, Natalia H Revelo, Richard Arts, Melissa Baerenfaenger, Fokje Zijlstra, Karin Huijben, Kimiyo Raymond, Kai Muru, Olga Fjodorova, Sander Pajusalu, Katrin Õunap, Martin ter Beest, Dirk Lefeber, Geert van den Bogaart

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Received Date: 10th April 20

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 protein regulation.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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