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

The identification of risk factors and their molecular contribution to MSP expands our understanding of disease mechanisms. Here, we describe a family with dominantly inherited MSP, in which a mutation in the serine/arginine repetitive matrix protein 2 gene (SRRM2) that co-segregates with disease, is identified.

SRRM2 is essential for nuclear speckle formation and a constitutive member of the RNA splicing machinery. To investigate how the mutation in SRRM2 might contribute to MSP 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 protein-protein interaction between SRRM2 and the splicing factor ACIN1.