{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSelenoprotein N (SelN), encoded by the SEPN1 gene, is an endoplasmic reticulum–resident selenoprotein uniquely implicated in a spectrum of congenital myopathies including multiminicore disease, rigid spine muscular dystrophy, congenital fiber‐type disproportion, and desmin‐related myopathies. Genetic studies have revealed that point mutations, ranging from missense and nonsense changes to those affecting regulatory elements—such as the SECIS and SRE domains required for the specialized co‐translational incorporation of selenocysteine—disrupt SelN expression and function. These alterations result in reduced protein levels and abnormal expression patterns in muscle tissue, underscoring the critical role of SelN in maintaining normal myofiber structure and function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctional experiments have further illuminated SelN’s role as a key regulator of intracellular calcium homeostasis. It operates as a calcium sensor within the endoplasmic reticulum by utilizing a luminal EF‐hand domain that dynamically alters its oligomeric state in response to calcium depletion. Through redox‐dependent interactions, SelN modulates the activity of major calcium channels—especially the ryanodine receptor (RyR)—and functionally couples with the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) to maintain proper calcium fluxes. These processes are essential not only for skeletal muscle excitation–contraction coupling but also for the regulation of oxidant stress signaling, thereby linking defective calcium and redox homeostasis to the pathogenesis of SEPN1‐related myopathies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its pivotal role in calcium sensing, SelN is emerging as a key mediator in muscle development, regeneration, and bioenergetics. Investigations in both animal models and patient-derived tissues have demonstrated that deficient SelN disrupts endoplasmic reticulum–mitochondria contacts, thereby impairing calcium transfer necessary for optimal mitochondrial function and ATP production. This bioenergetic failure is associated with muscle weakness, axial hypotonia, and the development of core lesions, while altered SelN splicing—potentially driven by exonization events—suggests additional layers of evolutionary and tissue‐specific regulation. Moreover, SelN deficiency appears to compromise satellite cell maintenance and modulate reactive oxygen species responses, factors that collectively contribute to the progressive clinical phenotype observed in SEPN1‐related myopathies, even extending to atypical late-onset cases. Such multifaceted roles emphasize the importance of SelN in sustaining muscle integrity and energy metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ana Ferreiro, Susana Quijano-Roy, Claire Pichereau, et al. 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