EMBO Molecular Medicine (Nov 2021)
BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy
- 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
Affiliations
- Sandra Donkervoort
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Niklas Krause
- Biochemistry III/Faculty of Chemistry, Bielefeld University
- Mykola Dergai
- Department of Fundamental Neurosciences, University of Lausanne
- Pomi Yun
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Judith Koliwer
- Biochemistry III/Faculty of Chemistry, Bielefeld University
- Svetlana Gorokhova
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Janelle Geist Hauserman
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Beryl B Cummings
- Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Ying Hu
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Rosemarie Smith
- Maine Medical Center
- Prech Uapinyoying
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Vijay S Ganesh
- Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Partha S Ghosh
- Department of Neurology, Boston Children's Hospital
- Kristin G Monaghan
- GeneDx
- Seby L Edassery
- Department of Neurology, Feinberg School of Medicine, Northwestern University
- Pia E Ferle
- Biochemistry III/Faculty of Chemistry, Bielefeld University
- Sarah Silverstein
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Katherine R Chao
- Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Molly Snyder
- Department of Neurology, Children's Health
- Sara Ellingwood
- Maine Medical Center
- Diana Bharucha‐Goebel
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Susan T Iannaccone
- Division of Pediatric Neurology, Departments of Pediatrics, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center
- Matteo Dal Peraro
- Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL)
- A Reghan Foley
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Jeffrey N Savas
- Department of Neurology, Feinberg School of Medicine, Northwestern University
- Véronique Bolduc
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Dirk Fasshauer
- Department of Fundamental Neurosciences, University of Lausanne
- Carsten G Bönnemann
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Michael Schwake
- Biochemistry III/Faculty of Chemistry, Bielefeld University
- DOI
- https://doi.org/10.15252/emmm.202013787
- Journal volume & issue
-
Vol. 13,
no. 12
pp. 1 – 17
Abstract
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.
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