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Journal Review: The Notch signaling pathway in skeletal muscle health and disease
Journal Review: The Notch signaling pathway in skeletal muscle health and disease

The Notch signaling pathway is a key regulator of skeletal muscle development and regeneration. Over the past decade, the discoveries of three new muscle disease genes have added a new dimension to the relationship between the Notch signaling pathway and skeletal muscle: MEGF10, POGLUT1, and JAG2. We review the clinical syndromes associated with pathogenic variants in each of these genes, known molec-ular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases. The phenotypes associated with two of these genes, POGLUT1 and JAG2, clearly fall within the realm of muscular dystrophy, whereas the third, MEGF10, is associated with a congenital myopathy/muscular dys-trophy overlap syndrome classically known as early-onset myopathy, areflexia, respi-ratory distress, and dysphagia. JAG2 is a canonical Notch ligand, POGLUT1 glycosylates the extracellular domain of Notch receptors, and MEGF10 interacts with the intracellular domain of NOTCH1. Additional genes and their encoded proteins relevant to muscle function and disease with links to the Notch signaling pathway include TRIM32, ATP2A1 (SERCA1), JAG1, PAX7, and NOTCH2NLC. There is enor-mous potential to identify convergent mechanisms of skeletal muscle disease and new therapeutic targets through further investigations of the Notch signaling path-way in the context of skeletal muscle development, maintenance, and disease.

1)Recognize the phenotypes of muscle disease produced by pathogenic variants in 3 different muscle disease genes involved in the Notch signaling pathway;
2)Be able to order appropriate genetic testing in these patients. 

The AANEM is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The AANEM designates this enduring material for a maximum of 1 AMA PRA Category 1 Credits TM.  Physicians should claim only the credit commensurate with the extent of their participation in the activity. Credit expires 11/10/2025.

None of the authors had any conflicts of interest to disclose.

Dorianmarie Vargas-Franco, PhD; Raghav Kalra, BS; Isabelle Draper, PhD; Christina A. Pacak, PhD; Atsushi Asakura, PhD; Peter B. Kang, MD
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