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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP (3-9, 5-6, and 5-7 to SN, MH, TI and IN) and by AMED under Grant Numbers JP23bm1223001s0102, JP23ek0109617s0402 (IN), JP23ak0101195s0101 (SN). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethic approval and consent to participate All clinical information and materials used in the present study were obtained for diagnostic purposes with written informed consent. The study was approved by the Ethics Committee of National Center of Neurology and Psychiatry (Approved No. A2019-123, A2019-124). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author, S.N., upon reasonable request.