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© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted., Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with short survival, mainly due to respiratory failure. A pathological repeat expansion in the C9orf72 gene is observed in about 10% of the European ALS population and is associated with a worse prognosis. Still, the exact function of this gene is unknown. To understand the role of the C9orf72 expansion in disease prognosis, we tested the impact of this mutation on the respiratory function in ALS., This study is included in the ONWebDUALS project (JPND- PS/0001/2013), an EU Joint Programme—Neurodegenerative Disease Research (JPND)—Fundação para a Ciência e Tecnologia initiative. VAC was independently funded by a PhD fellowship (PD/BD/105852/2014) from Fundação para a Ciência e Tecnologia, Portugal.

Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including inNUP50encoding for the nucleopore basket protein NUP50. Independently, rare variants inNUP50were associated with ALS risk (P = 3.71.10−03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying aNUP50frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects inDrosophilaand zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.