دورية أكاديمية
BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy
| العنوان: | BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy |
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| المؤلفون: | Sandra Donkervoort, Niklas Krause, Mykola Dergai, Pomi Yun, Judith Koliwer, Svetlana Gorokhova, Janelle Geist Hauserman, Beryl B Cummings, Ying Hu, Rosemarie Smith, Prech Uapinyoying, Vijay S Ganesh, Partha S Ghosh, Kristin G Monaghan, Seby L Edassery, Pia E Ferle, Sarah Silverstein, Katherine R Chao, Molly Snyder, Sara Ellingwood, Diana Bharucha‐Goebel, Susan T Iannaccone, Matteo Dal Peraro, A Reghan Foley, Jeffrey N Savas, Véronique Bolduc, Dirk Fasshauer, Carsten G Bönnemann, Michael Schwake |
| المصدر: | EMBO Molecular Medicine, Vol 13, Iss 12, Pp n/a-n/a (2021) |
| بيانات النشر: | Springer Nature, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Medicine (General) LCC:Genetics |
| مصطلحات موضوعية: | BET1, epilepsy, GOSR2, muscular dystrophy, SNARE, Medicine (General), R5-920, Genetics, QH426-470 |
| الوصف: | Abstract BET1 is required, together with its SNARE complex partners GOSR2, SEC22b, and Syntaxin‐5 for fusion of endoplasmic reticulum‐derived vesicles with the ER‐Golgi intermediate compartment (ERGIC) and the cis‐Golgi. Here, we report three individuals, from two families, with severe congenital muscular dystrophy (CMD) and biallelic variants in BET1 (P1 p.(Asp68His)/p.(Ala45Valfs*2); P2 and P3 homozygous p.(Ile51Ser)). Due to aberrant splicing and frameshifting, the variants in P1 result in low BET1 protein levels and impaired ER‐to‐Golgi transport. Since in silico modeling suggested that p.(Ile51Ser) interferes with binding to interaction partners other than SNARE complex subunits, we set off and identified novel BET1 interaction partners with low affinity for p.(Ile51Ser) BET1 protein compared to wild‐type, among them ERGIC‐53. The BET1/ERGIC‐53 interaction was validated by endogenous co‐immunoprecipitation with both proteins colocalizing to the ERGIC compartment. Mislocalization of ERGIC‐53 was observed in P1 and P2’s derived fibroblasts; while in the p.(Ile51Ser) P2 fibroblasts specifically, mutant BET1 was also mislocalized along with ERGIC‐53. Thus, we establish BET1 as a novel CMD/epilepsy gene and confirm the emerging role of ER/Golgi SNAREs in CMD. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1757-4684 1757-4676 |
| العلاقة: | https://doaj.org/toc/1757-4676Test; https://doaj.org/toc/1757-4684Test |
| DOI: | 10.15252/emmm.202013787 |
| الوصول الحر: | https://doaj.org/article/36e02f0c64b8417881fabf19320857cfTest |
| رقم الانضمام: | edsdoj.36e02f0c64b8417881fabf19320857cf |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17574684 17574676 |
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| DOI: | 10.15252/emmm.202013787 |