A mutation in the nuclear speckle and splicing factor SRRM2 is associated with multisystem proteinopathy and causes dysregulation of synapse-associated genes

Multisystem proteinopathy (MSP) is a pleiotropic degenerative disorder which affects the nervous system, muscles, and bones. 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 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. Transcriptome studies further revealed widespread differential gene expression, which converged on the dysregulation of synapse-associated pathways. Together, our findings identify SRRM2 as a novel MSP risk factor and provide mechanistic insights into how its mutation can be linked to MSP pathology.