Clinical and functional characterization of a new muscular dystrophy caused by novel recessive SNUPN pathogenic variants

Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders characterized by progressive muscle weakness and degeneration. This study presents a comprehensive investigation of a novel muscular dystrophy phenotype associated to germline recessive mutations in the SNUPN gene, identified in 21 patients from 18 unrelated families. Clinically, the affected individuals exhibited progressive muscle weakness with a broad spectrum of severity, ranging from mild symptoms and retained ambulation to severe early-onset muscular dystrophy leading to premature death from respiratory complications. Beyond muscular dystrophy, several patients displayed extra-muscular manifestations, notably neurological deficits, including cerebellar atrophy and congenital cataracts, reflecting broader systemic implications of SNUPN mutations. SNUPN encodes the SNURPORTIN-1 (SPN1) protein, which plays a critical role in the nuclear import of uridine-rich small nuclear ribonucleoproteins (UsnRNPs), crucial components of the spliceosome machinery. Most identified mutations clustered at the C-terminus of the SPN1 protein, highlighting its critical functional role and suggesting it as a potential mutational hotspot. Functional analyses demonstrated that defective SPN1 impairs the nuclear import of UsnRNPs, causing aberrant alternative splicing of numerous genes implicated in muscle structure and function. This aberrant splicing affected critical muscle-related proteins, including extracellular matrix components, sarcolemmal proteins, and cytoskeletal elements, likely contributing to muscle fiber degeneration, fibrosis, and functional impairment. Furthermore, this study uncovered novel insights into SPN1 protein biology, particularly its self-oligomerization and interaction with the survival motor neuron (SMN) protein complex. Disrupted SPN1-SMN interaction and autophagic dysregulation were observed, potentially suggesting these pathways may play a key role in the muscular dystrophy pathogenesis. Aberrant accumulation of autophagy markers (LC3-II and p62) in patient muscle tissues and cell lines further underscored this dysregulation. Comparative analysis with concurrently published data from independent cohorts supported our findings, reinforcing the genotype-phenotype correlations and highlighting novel disease mechanisms. Collectively, this research significantly expands the genetic landscape of muscular dystrophies by characterizing SNUPN-related muscular dystrophy at clinical, molecular, and functional levels. Future studies employing animal models and extended patient cohorts are essential to further deepen the understanding of SNUPN pathology, unravel the intricate molecular mechanisms, and facilitate the development of targeted therapeutic strategies.