Genetic SNUPN variants cause spinocerebellar atrophy by disrupting global splicing in Purkinje cells

Abstract

We identified genetic variants in the SNUPN gene, which encodes the adapter protein snurportin-1 for the nuclear import of U1 snRNPs, in two families affected by spinocerebellar ataxia. We have elucidated the pathogenicity of these variants and the molecular pathomechanisms underlying this disease by assessing mutant snurportin-1 properties in vitro, cerebella at the morphological and molecular levels ex vivo, and motor functions in Snupn-variant knocked-in mice in vivo. Mutant snurportin-1 impaired nuclear-cytosol shuttling, leading to defective nuclear transport of U1 snRNPs in cerebellar Purkinje cells. This resulted in aberrant splicing and expression of genes essential for Purkinje cell development and impaired dendrite formation. The malformation of Purkinje cell dendrites resulted in hypoplasia and premature migration of granule cell precursors and interneurons, leading to abnormal lobe development and atrophy in the cerebellum.