Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies
| Autor: | Luciano A. Abriata, Matteo Dal Peraro, Judith Koliwer, Gabriele Fischer von Mollard, Michael Schwake, Jörn Michael Völker, Yves Mingard, Dirk Fasshauer, Daniel Ysselstein, Dimitri Krainc, Mykola Dergai |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Amino Acid Motifs Mutant Golgi Apparatus lcsh:Medicine Medicine (miscellaneous) GS27 Endoplasmic Reticulum Compound heterozygosity 0302 clinical medicine Immunology and Microbiology (miscellaneous) Membrin Genetics Bos1 Qb-SNARE Proteins 3. Good health symbols medicine.symptom SNARE Proteins SNARE complex Research Article lcsh:RB1-214 Saccharomyces cerevisiae Proteins Ataxia Neuroscience (miscellaneous) Saccharomyces cerevisiae Biology GOSR2 PME Progressive myoclonus epilepsies Arginine General Biochemistry Genetics and Molecular Biology 03 medical and health sciences symbols.namesake lcsh:Pathology medicine Humans Computer Simulation Amino Acid Sequence Gene lcsh:R Golgi apparatus Myoclonic Epilepsies Progressive Yeast 030104 developmental biology Mutation Myoclonus 030217 neurology & neurosurgery |
| Zdroj: | Disease Models & Mechanisms, Vol 10, Iss 12, Pp 1391-1398 (2017) Disease Models & Mechanisms Disease models & mechanisms, vol. 10, no. 12, pp. 1391-1398 |
| DOI: | 10.1242/dmm.029132 |
| Popis: | 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 Qb-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. Summary: Mutations in the Qb-SNARE GOSR2 cause progressive myoclonus epilepsies. The authors report the effect of two mutations on SNARE function to investigate their correlation with progression and severity of disease. |
| Databáze: | OpenAIRE |
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