SMN deficiency-induced alternative splicing dysregulation in cardiac defects.

Abstract

AIMS: Spinal muscular atrophy (SMA) caused by reduced survival motor neuron (SMN) protein, is increasingly recognized as a multisystem disorder with cardiac involvement. We aimed to determine how SMN deficiency disrupts postnatal cardiac development and to explore the potential molecular mechanism linking SMN loss to cardiomyocyte dysfunction. MATERIALS AND METHODS: A severe Taiwanese SMA mice model was used to evaluate postnatal cardiac growth and function. Cardiac phenotypes were characterized by histological analysis, transmission electron microscopy, and echocardiography. Transcriptomic profiling and alternative splicing analyses were performed in hearts collected at postnatal day 7, with key events validated by RT-PCR and qPCR. In parallel, SMN- or SmB-deficient cardiomyocyte models were employed to investigate snRNP assembly-dependent mechanisms. KEY FINDINGS: SMA mice exhibited impaired cardiac development and reduced contractile function, accompanied by decreased cardiomyocyte proliferation and increased apoptosis. Alternative splicing of Mdm2 and Mdm4 was markedly dysregulated in SMA hearts, coinciding with upregulation of p53 pathway targets. Mechanistically, SMN deficiency disrupted spliceosomal snRNP assembly, associated with altered SmB expression and localization. Finally, SmB depletion phenocopied Mdm2/Mdm4 mis-splicing and activated p53 signaling in cardiomyocytes. SIGNIFICANCE: These findings uncover an SMN-SmB-snRNP assembly pathway that links SMN deficiency to aberrant Mdm2/Mdm4 splicing and consequent p53 activation, suggesting a possible mechanistic explanation for SMA-associated cardiac pathology and highlighting spliceosome-directed interventions as a potential adjunct to existing SMA gene therapies.