Authors: Salim Megat, Natalia Mora, Jason Sanogo, Olga Roman, Alberto Catanese, Najwa Ouali Alami, Axel Freischmidt, Xhuljana Mingaj, Hortense De Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Van Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Van Eijk, Jan H. Veldink, , Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Le Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier, Luc Dupuis
Published: 2023-01-21
DOI: 10.1038/s41467-022-35724-1
Source: Full article
AbstractAmyotrophic 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.