BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy.
BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy.
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DOI：
10.15252/emmm.202013787
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发表时间：
2021-12-07
影响因子：
11.1
通讯作者：
Schwake M
中科院分区：
文献类型：
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作者：
Donkervoort S;Krause N;Dergai M;Yun P;Koliwer J;Gorokhova S;Geist Hauserman J;Cummings BB;Hu Y;Smith R;Uapinyoying P;Ganesh VS;Ghosh PS;Monaghan KG;Edassery SL;Ferle PE;Silverstein S;Chao KR;Snyder M;Ellingwood S;Bharucha-Goebel D;Iannaccone ST;Dal Peraro M;Foley AR;Savas JN;Bolduc V;Fasshauer D;Bönnemann CG;Schwake M
需要BET 1与其SNARE复合物伙伴GOSR 2，SEC 22 b和Syntaxin-5一起用于内质网衍生的囊泡与ER-高尔基体中间室（ERGIC）和顺-高尔基体的融合。在这里，我们报告了三个人，从两个家庭，与严重的先天性肌营养不良症（CMD）和双等位基因变异的BET 1（P1 p。（Asp68His）/p.（Ala 45 Valfs *2）; P2和P3纯合子p.（Ile51Ser））。由于异常剪接和移码，P1中的变体导致BET 1蛋白水平降低和ER至高尔基体转运受损。由于计算机模拟表明，p。（Ile 51 Ser）干扰与SNARE复合物亚基以外的相互作用伴侣的结合，我们启动并鉴定了对p.（Ile 51 Ser）BET 1蛋白与野生型相比，其中包括ERGIC-53。通过内源性免疫共沉淀验证了BET 1/ERGIC-53相互作用，两种蛋白质共定位于ERGIC区室。ERGIC-53在P1和P2来源的成纤维细胞中观察到错误定位;特别是在（Ile 51 Ser）P2成纤维细胞中，突变型BET 1也与ERGIC-53一起沿着错误定位。因此，我们确定BET 1作为一种新的CMD/癫痫基因，并证实ER/高尔基体SNARE在CMD中的新作用。这项研究描述了三名患有进行性早发性先天性肌营养不良症的患者，其中一名患者患有由BET 1基因中的双等位基因变体引起的额外癫痫。BET 1，沿着它的SNARE复合物伙伴，对于ER到高尔基体的运输是必不可少的。
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. This study describes three individuals with a progressive early‐onset congenital muscular dystrophy, and additional epilepsy in one, caused by biallelic variants in the BET1 gene. BET1, along with its SNARE complex partners, is essential for ER‐to‐Golgi trafficking.