A point mutation in the nuclear speckle protein and splicing factor SRRM2 is associated with amyotrophic lateral sclerosis and causes dysregulation of synapse-associated genes

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neuron function. ALS is a multifactorial disease which can originate from complex genetic and environmental factors. The identification of risk factors and their molecular contribution to ALS expand our understanding of the disease mechanism. Here, we describe a family with dominantly inherited degeneration, which carries a mutation in the serine/arginine repetitive matrix 2 gene (SRRM2). SRRM2 is essential for nuclear speckle formation and a constitutive member of the RNA splicing machinery. To investigate how the mutation in SRRM2 contributed to the ALS pathogenesis, we examined its effect on a model cell line, where the point mutation was introduced in the endogenous gene. Surprisingly, we found that the resulting single amino acid exchange led to the loss of one protein-protein interaction, between SRRM2 and the splicing factor ACIN1. Transcriptome studies further revealed wide-spread differential gene expression, which converged on the dysregulation of synapse-associated pathways. Together, our findings identify SRRM2 as a novel ALS risk factor and provide mechanistic insights into how its mutation can be linked to ALS pathology.