مورد إلكتروني
Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability
| العنوان: | Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability |
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| المؤلفون: | Cacace, R., Heeman, B., Mossevelde, S., Roeck, A., Hoogmartens, J., Rijk, P. (Peter) de, Gossye, H., de Vos, K., Coster, W. de, Strazisar, M., De Baets, G., Schymkowitz, J., Rousseau, M.F. (Francois), Geerts, N., Pooter, T. (Tim) de, Peeters, K. (Karin), Sieben, A., Martin, J. (John), Engelborghs, S. (Sebastiaan), Salmon, E. (E.), Santens, P. (Patrick), Vandenberghe, R. (Rik), Cras, P. (Patrick), Deyn, P.P. (Peter) de, Swieten, J.C. (John) van, Duijn, C.M., Zee, J.A. (Johan) van der, Sleegers, K. (Kristel), Broeckhoven, C. (Christine) van, Goeman, J., Crols, R., Nuytten, D., De Bleecker, J.L., Van Langenhove, T, Ivanoiu, A., Deryck, O., Bergmans, B, Versijpt, J., Michotte, A., Delbeck, J., Willems, C., De Klippel, N. |
| بيانات النشر: | 2019-03-14 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal fring as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family signifcantly linked to 7q36. We identifed and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identifed signifcantly more rare variants—nonsense, frameshift, and missense—in early-onset Alzheimer’s disease (EOAD, p value=0.03, OR=2.21 95% CI 1.05–4.82) and frontotemporal dementia (FTD, p=0.006, OR=2.59, 95% CI 1.28–5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p<0.001 and p<0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause |
| مصطلحات الفهرس: | Neurodegenerative brain diseases · Dementia · DPP6 · Hyperexcitability · Whole genome sequencing · Oxford nanopore technologies (ONT) PromethION, info:eu-repo/semantics/article |
| DOI: | 10.1007.s00401-019-01976-3 |
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| الإتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | application/pdf Acta Neuropathologica vol. 137 no. 6, pp. 901-918 English |
| أرقام أخرى: | QGQ oai:repub.eur.nl:116798 doi:10.1007/s00401-019-01976-3 urn:hdl:1765/116798 1111586292 |
| المصدر المساهم: | ERASMUS UNIVERSITEIT ROTTERDAM From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1111586292 |
| قاعدة البيانات: | OAIster |
| DOI: | 10.1007.s00401-019-01976-3 |
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