PT  - JOURNAL ARTICLE
AU  - Roman Praschberger
AU  - Simon A. Lowe
AU  - Nancy T. Malintan
AU  - Henry Houlden
AU  - Dimitri M. Kullmann
AU  - Maria M. Usowicz
AU  - Shyam S. Krishnakumar
AU  - James J.L. Hodge
AU  - James E. Rothman
AU  - James E.C. Jepson
TI  - Mutations in Membrin/<em>GOSR2</em> reveal stringent secretory pathway demands of dendritic growth and synaptic integrity
AID  - 10.1101/142679
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 142679
4099  - http://biorxiv.org/content/early/2017/05/26/142679.short
4100  - http://biorxiv.org/content/early/2017/05/26/142679.full
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.