TY - JOUR
T1 - BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy
AU - Donkervoort, Sandra
AU - Krause, Niklas
AU - Dergai, Mykola
AU - Yun, Pomi
AU - Koliwer, Judith
AU - Gorokhova, Svetlana
AU - Geist Hauserman, Janelle
AU - Cummings, Beryl B.
AU - Hu, Ying
AU - Smith, Rosemarie
AU - Uapinyoying, Prech
AU - Ganesh, Vijay S.
AU - Ghosh, Partha S.
AU - Monaghan, Kristin G.
AU - Edassery, Seby L.
AU - Ferle, Pia E.
AU - Silverstein, Sarah
AU - Chao, Katherine R.
AU - Snyder, Molly
AU - Ellingwood, Sara
AU - Bharucha-Goebel, Diana
AU - Iannaccone, Susan T.
AU - Dal Peraro, Matteo
AU - Foley, A. Reghan
AU - Savas, Jeffrey N.
AU - Bolduc, Véronique
AU - Fasshauer, Dirk
AU - Bönnemann, Carsten G.
AU - Schwake, Michael
N1 - Funding Information:
We would like to thank the families for their participation. We would like to thank Samantha Baxter and Kirsty McWalter for their help with the ClinVar submission and Rupleen Kaur for her help in the laboratory. We are grateful to Hans Dieter Schmitt and Andrew Peden for providing the Bet1-1 (BSH-7C) yeast strain and the ER-to-Golgi transport reporter construct and HeLa-M cells, respectively. The work in C.G. Bönnemann’s laboratory is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. M. Schwake receives funding from the Deutsche Forschungsgemeinschaft (SCHW866/5-1 and 5-2) and a Heisenberg fellowship (SCHW866/6-1 and 7-1). D. Fasshauer receives funding from the Swiss National Science Foundation (#31003A_182732). We would like to thank the NIH Intramural Sequencing staff for their help with the exome analysis. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, the National Heart, Lung and Blood Institute and grant UM1HG008900 to Daniel MacArthur and Heidi Rehm. This study makes use of data shared through the seqr platform with funding provided by National Institutes of Health grants R01HG009141 and UM1HG008900. The authors would like to thank the University of Washington Center for Mendelian Genomics and all contributors to Geno2MP for use of data included in Geno2MP. Open Access funding enabled and organized by Projekt DEAL.
Funding Information:
We would like to thank the families for their participation. We would like to thank Samantha Baxter and Kirsty McWalter for their help with the ClinVar submission and Rupleen Kaur for her help in the laboratory. We are grateful to Hans Dieter Schmitt and Andrew Peden for providing the Bet1‐1 (BSH‐7C) yeast strain and the ER‐to‐Golgi transport reporter construct and HeLa‐M cells, respectively. The work in C.G. Bönnemann’s laboratory is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. M. Schwake receives funding from the Deutsche Forschungsgemeinschaft (SCHW866/5‐1 and 5‐2) and a Heisenberg fellowship (SCHW866/6‐1 and 7‐1). D. Fasshauer receives funding from the Swiss National Science Foundation (#31003A_182732). We would like to thank the NIH Intramural Sequencing staff for their help with the exome analysis. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, the National Heart, Lung and Blood Institute and grant UM1HG008900 to Daniel MacArthur and Heidi Rehm. This study makes use of data shared through the seqr platform with funding provided by National Institutes of Health grants R01HG009141 and UM1HG008900. The authors would like to thank the University of Washington Center for Mendelian Genomics and all contributors to Geno2MP for use of data included in Geno2MP. Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2021/12/7
Y1 - 2021/12/7
N2 - 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.
AB - 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.
KW - BET1
KW - GOSR2
KW - SNARE
KW - epilepsy
KW - muscular dystrophy
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U2 - 10.15252/emmm.202013787
DO - 10.15252/emmm.202013787
M3 - Article
C2 - 34779586
AN - SCOPUS:85119334790
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
M1 - e13787
ER -