Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies

Völker JM, Dergai M, Abriata LA, Mingard Y, Ysselstein D, Krainc D, Dal Peraro M, Fischer von Mollard G, Fasshauer D, Koliwer J, Schwake M (2017)
DISEASE MODELS & MECHANISMS 10(12): 1391-1398.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
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Autor*in
Völker, Jörn MichaelUniBi; Dergai, Mykola; Abriata, Luciano A.; Mingard, Yves; Ysselstein, Daniel; Krainc, Dimitri; Dal Peraro, Matteo; Fischer von Mollard, GabrieleUniBi; Fasshauer, Dirk; Koliwer, JudithUniBi; Schwake, MichaelUniBi
Abstract / Bemerkung
Progressive myoclonus epilepsies (PMEs) are inherited disorders characterized by myoclonus, generalized tonic-clonic seizures, and ataxia. One of the genes that is associated with PME is the ER-to-Golgi Q(b)-SNARE GOSR2, which forms a SNARE complex with syntaxin-5, Bet1 and Sec22b. Most PME patients are homozygous for a p.Gly144Trp mutation and develop similar clinical presentations. Recently, a patient who was compound heterozygous for p.Gly144Trp and a previously unseen p.Lys164del mutation was identified. Because 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 ortholog 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, but with partly reduced activity. Molecular dynamics (MD) 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 syntaxin-5. 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.
Stichworte
Progressive myoclonus epilepsies; PME; GOSR2; Membrin; GS27; Bos1
Erscheinungsjahr
2017
Zeitschriftentitel
DISEASE MODELS & MECHANISMS
Band
10
Ausgabe
12
Seite(n)
1391-1398
ISSN
1754-8403
eISSN
1754-8411
Page URI
https://pub.uni-bielefeld.de/record/2916411

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Völker JM, Dergai M, Abriata LA, et al. Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies. DISEASE MODELS & MECHANISMS. 2017;10(12):1391-1398.
Völker, J. M., Dergai, M., Abriata, L. A., Mingard, Y., Ysselstein, D., Krainc, D., Dal Peraro, M., et al. (2017). Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies. DISEASE MODELS & MECHANISMS, 10(12), 1391-1398. doi:10.1242/dmm.029132
Völker, J. M., Dergai, M., Abriata, L. A., Mingard, Y., Ysselstein, D., Krainc, D., Dal Peraro, M., Fischer von Mollard, G., Fasshauer, D., Koliwer, J., et al. (2017). Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies. DISEASE MODELS & MECHANISMS 10, 1391-1398.
Völker, J.M., et al., 2017. Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies. DISEASE MODELS & MECHANISMS, 10(12), p 1391-1398.
J.M. Völker, et al., “Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies”, DISEASE MODELS & MECHANISMS, vol. 10, 2017, pp. 1391-1398.
Völker, J.M., Dergai, M., Abriata, L.A., Mingard, Y., Ysselstein, D., Krainc, D., Dal Peraro, M., Fischer von Mollard, G., Fasshauer, D., Koliwer, J., Schwake, M.: Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies. DISEASE MODELS & MECHANISMS. 10, 1391-1398 (2017).
Völker, Jörn Michael, Dergai, Mykola, Abriata, Luciano A., Mingard, Yves, Ysselstein, Daniel, Krainc, Dimitri, Dal Peraro, Matteo, Fischer von Mollard, Gabriele, Fasshauer, Dirk, Koliwer, Judith, and Schwake, Michael. “Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies”. DISEASE MODELS & MECHANISMS 10.12 (2017): 1391-1398.

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