RT Journal Article SR Electronic T1 Mutations in Membrin/GOSR2 reveal stringent secretory pathway demands of dendritic growth and synaptic integrity JF bioRxiv FD Cold Spring Harbor Laboratory SP 142679 DO 10.1101/142679 A1 Roman Praschberger A1 Simon A. Lowe A1 Nancy T. Malintan A1 Henry Houlden A1 Dimitri M. Kullmann A1 Maria M. Usowicz A1 Shyam S. Krishnakumar A1 James J.L. Hodge A1 James E. Rothman A1 James E.C. Jepson YR 2017 UL http://biorxiv.org/content/early/2017/05/26/142679.abstract AB Mutations in the Golgi SNARE protein Membrin (encoded by the GOSR2 gene) cause progressive myoclonus epilepsy (PME). Membrin is a ubiquitously important protein mediating ER-to-Golgi membrane fusion, and hence it is unclear how these mutations result in a disorder restricted to the nervous system. Here we use a multi-layered strategy to elucidate the consequences of Membrin mutations from protein to neuron. We show that the pathogenic mutations cause partial reductions in SNARE-mediated membrane fusion. Importantly, these alterations were sufficient to profoundly impair dendritic growth in novel Drosophila models of GOSR2-PME. We also observed axonal trafficking abnormalities in this model, as well as synaptic malformations, trans-synaptic instability and hyperactive synaptic transmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a previously uncharacterized role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME.