Genetic disruption of satellite cell function underlying congenital myopathies.

Abstract

Congenital myopathies are a group of genetically heterogeneous neuromuscular disorders characterized by early-onset hypotonia and muscle weakness. While many congenital myopathies have historically been attributed to structural defects in muscle fibers, accumulating evidence reveals that dysfunction of satellite cells-the resident stem cells essential for muscle growth and regeneration-can also cause congenital myopathy. In this review, we focus on four genes critical for satellite cell biology: PAX7, MYOD1, MEGF10, and MYMK, and discuss how pathogenic variants in these genes contribute to muscle pathology. Mutations in PAX7, a transcription factor essential for satellite cell specification and maintenance, have been identified in patients with progressive congenital myopathy and scoliosis. MYOD1 variants affect the transcriptional regulation of myogenic differentiation and have been reported in individuals with congenital muscle hypoplasia. Loss-of-function variants in MEGF10, which mediates satellite cell proliferation, result in early-onset myopathy characterized by severe weakness and areflexia. Mutations in MYMK, essential for myoblast fusion, lead to congenital myopathy with facial and axial weakness. Together, these studies illustrate that distinct steps in satellite cell function-including specification, commitment, proliferation, and fusion-are critical for normal muscle development and maintenance. Recognizing that genetic defects affecting any of these processes can lead to congenital myopathies, redefining the disease spectrum beyond purely structural muscle disorders. Expanding our understanding of satellite cell biology will be key to elucidating the full spectrum of congenital myopathies and identifying targeted therapeutic strategies.