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

Sandra Donkervoort (1) , Niklas Krause (2) , Mykola Dergai (3) , Pomi Yun (1) , Judith Koliwer (2) , Svetlana Gorokhova (4, 5, 1) , Janelle Geist Hauserman (1) , Beryl Cummings (6) , Ying Hu (1) , Rosemarie Smith (7) , Prech Uapinyoying (1, 8) , Vijay Ganesh (6, 9) , Partha Ghosh (10) , Kristin Monaghan (11) , Seby Edassery (12) , Pia Ferle (2) , Sarah Silverstein (1, 13, 14) , Katherine Chao (6) , Molly Snyder (15) , Sara Ellingwood (7) , Diana Bharucha‐goebel (1, 8) , Susan Iannaccone (16) , Matteo Dal Peraro (17) , a Reghan Foley (1) , Jeffrey Savas (12) , Véronique Bolduc (1) , Dirk Fasshauer (3) , Carsten Bönnemann (1) , Michael Schwake (2, 12)

1 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
2 Universität Bielefeld = Bielefeld University
3 UNIL - Université de Lausanne = University of Lausanne
4 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
5 Département de génétique médicale [Hôpital de la Timone - APHM]
6 BROAD INSTITUTE - Broad Institute of MIT and Harvard
7 Maine Medical Center
8 Children's National Medical Center
9 HMS - Harvard Medical School [Boston]
10 Boston Children's Hospital
11 GeneDx [Gaithersburg, MD, USA]
12 Northwestern University [Chicago, Ill. USA]
13 NJMS - Rutgers New Jersey Medical School
14 NHGRI - National Human Genome Research Institute
15 Stanford Children's Health
16 University of Texas Southwestern Medical Center [Dallas]
17 EPFL - Ecole Polytechnique Fédérale de Lausanne

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.

Keywords: BET1; GOSR2; SNARE; epilepsy; muscular dystrophy

Domains: Life Sciences [q-bio]; Genetics; Life Sciences [q-bio]; Human health and pathology

Sandra Donkervoort, Niklas Krause, Mykola Dergai, Pomi Yun, Judith Koliwer, et al.. BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy. EMBO Molecular Medicine, 2021, 13 (12), ⟨10.15252/emmm.202013787⟩. ⟨hal-03662312⟩