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One of the genes that are associated with PME is the ER-to-Golgi Qb-SNARE GOSR2, which forms a SNARE complex with Syntaxin5, Bet1 and Sec22b. Most PME patients are homo\u00adzygous for a p.Gly144Trp mutation and develop similar clinical presentations. Recently, a patient who was compound heterozygous for the p.Gly144Trp and a novel p.Lys164del mutation was identified. Since this patient presented with a milder disease phenotype, we hypothesized that the p.Lys164del mutation may be less severe compared to p.Gly144Trp. To characterize the effect of the p.Gly144Trp and p.Lys164del mutations, both of which are present in the SNARE motif of GOSR2, we examined the corresponding mutations in the yeast orthologue Bos1. Yeasts expressing the orthologous mutants in Bos1 showed impaired growth, suggesting a partial loss of function, which was more severe for the Bos1 p.Gly176Trp mutation. Using anisotropy and gel filtration, we report that Bos1 p.Gly176Trp and p.Arg196del are capable of complex formation, however with partly reduced activity. Molecular dynamics simulations showed that the hydrophobic core, which triggers SNARE complex formation, is compromised due to the glycine to tryptophan substitution in both GOSR2 and Bos1. In contrast, the deletion of residue p.Lys164 (or p.Arg196del in Bos1) interferes with the formation of hydrogen bonds between GOSR2 and Syntaxin5. Despite these perturbations, all SNARE complexes stayed intact during longer simulations. Thus, our data suggest that the milder course of disease in compound heterozygous PME is due to less severe impairment of the SNARE function.<\/jats:p>","DOI":"10.1242\/dmm.029132","type":"journal-article","created":{"date-parts":[[2017,10,6]],"date-time":"2017-10-06T00:30:16Z","timestamp":1507249816000},"source":"Crossref","is-referenced-by-count":9,"title":["Functional assays for the assessment of the pathogenicity of variants in GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies"],"prefix":"10.1242","author":[{"given":"J\u00f6rn M.","family":"V\u00f6lker","sequence":"first","affiliation":[{"name":"Biochemistry III\/ Faculty of Chemistry, Bielefeld University, Universit\u00e4tsstr. 25, 33615 Bielefeld, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mykola","family":"Dergai","sequence":"additional","affiliation":[{"name":"Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luciano A.","family":"Abriata","sequence":"additional","affiliation":[{"name":"Institute of Bioengineering, School of Life Sciences, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland and Swiss Institute of Bioinformatics (SIB), CH-1015 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves","family":"Mingard","sequence":"additional","affiliation":[{"name":"Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Ysselstein","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, 60611 Chicago, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitri","family":"Krainc","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, 60611 Chicago, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Dal Peraro","sequence":"additional","affiliation":[{"name":"Institute of Bioengineering, School of Life Sciences, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland and Swiss Institute of Bioinformatics (SIB), CH-1015 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele Fischer","family":"von Mollard","sequence":"additional","affiliation":[{"name":"Biochemistry III\/ Faculty of Chemistry, Bielefeld University, Universit\u00e4tsstr. 25, 33615 Bielefeld, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Fasshauer","sequence":"additional","affiliation":[{"name":"Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Koliwer","sequence":"additional","affiliation":[{"name":"Biochemistry III\/ Faculty of Chemistry, Bielefeld University, Universit\u00e4tsstr. 25, 33615 Bielefeld, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4173-2166","authenticated-orcid":false,"given":"Michael","family":"Schwake","sequence":"additional","affiliation":[{"name":"Biochemistry III\/ Faculty of Chemistry, Bielefeld University, Universit\u00e4tsstr. 25, 33615 Bielefeld, Germany"},{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, 60611 Chicago, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2017,1,1]]},"reference":[{"key":"2021042513014152200_DMM029132C1","doi-asserted-by":"publisher","first-page":"39150","DOI":"10.1074\/jbc.M105833200","article-title":"The coatomer-interacting protein Dsl1p is required for Golgi-to-endoplasmic reticulum retrieval in yeast","volume":"276","author":"Andag","year":"2001","journal-title":"J. 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