BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy

Donkervoort S, Krause N, Dergai M, Yun P, Koliwer J, Gorokhova S, Hauserman JG, Cummings BB, Hu Y, Smith R, Uapinyoying P, et al. (2021)
EMBO Molecular Medicine : e13787.

Zeitschriftenaufsatz | E-Veröff. vor dem Druck | Englisch
 
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Autor*in
Donkervoort, Sandra; Krause, NiklasUniBi; Dergai, Mykola; Yun, Pomi; Koliwer, Judith; Gorokhova, Svetlana; Hauserman, Janelle Geist; Cummings, Beryl B.; Hu, Ying; Smith, Rosemarie; Uapinyoying, Prech; Ganesh, Vijay S.
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Abstract / Bemerkung
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.
Stichworte
BET1; epilepsy; GOSR2; muscular dystrophy; SNARE
Erscheinungsjahr
2021
Zeitschriftentitel
EMBO Molecular Medicine
Art.-Nr.
e13787
ISSN
1757-4676
eISSN
1757-4684
Page URI
https://pub.uni-bielefeld.de/record/2959493

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Donkervoort S, Krause N, Dergai M, et al. BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy. EMBO Molecular Medicine . 2021: e13787.
Donkervoort, S., Krause, N., Dergai, M., Yun, P., Koliwer, J., Gorokhova, S., Hauserman, J. G., et al. (2021). BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy. EMBO Molecular Medicine , e13787. https://doi.org/10.15252/emmm.202013787
Donkervoort, S., Krause, N., Dergai, M., Yun, P., Koliwer, J., Gorokhova, S., Hauserman, J. G., Cummings, B. B., Hu, Y., Smith, R., et al. (2021). BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy. EMBO Molecular Medicine :e13787.
Donkervoort, S., et al., 2021. BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy. EMBO Molecular Medicine , : e13787.
S. Donkervoort, et al., “BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy”, EMBO Molecular Medicine , 2021, : e13787.
Donkervoort, S., Krause, N., Dergai, M., Yun, P., Koliwer, J., Gorokhova, S., Hauserman, J.G., Cummings, B.B., Hu, Y., Smith, R., Uapinyoying, P., Ganesh, V.S., Ghosh, P.S., Monaghan, K.G., Edassery, S.L., Ferle, P., Silverstein, S., Chao, K.R., Snyder, M., Ellingwood, S., Bharucha-Goebel, D., Iannaccone, S.T., Dal Peraro, M., Foley, A.R., Savas, J.N., Bolduc, V., Fasshauer, D., Bonnemann, C.G., Schwake, M.: BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy. EMBO Molecular Medicine . : e13787 (2021).
Donkervoort, Sandra, Krause, Niklas, Dergai, Mykola, Yun, Pomi, Koliwer, Judith, Gorokhova, Svetlana, Hauserman, Janelle Geist, Cummings, Beryl B., Hu, Ying, Smith, Rosemarie, Uapinyoying, Prech, Ganesh, Vijay S., Ghosh, Partha S., Monaghan, Kristin G., Edassery, Seby L., Ferle, Pia, Silverstein, Sarah, Chao, Katherine R., Snyder, Molly, Ellingwood, Sara, Bharucha-Goebel, Diana, Iannaccone, Susan T., Dal Peraro, Matteo, Foley, A. Reghan, Savas, Jeffrey N., Bolduc, Veronique, Fasshauer, Dirk, Bonnemann, Carsten G., and Schwake, Michael. “BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy”. EMBO Molecular Medicine (2021): e13787.

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