Key result
CRISPR EMD gene correction reduces mislocalized nuclei ~27% in EDMD1 myotubes by restoring emerin expression.
Absolute Event Rate: 35% vs 48%
Emerin is required for Nuclear Envelope-MTOC organization in differentiating skeletal muscle cells, suggesting its disruption is a key pathogenetic event in Emery-Dreifuss Muscular Dystrophy.
Supports emerin disruption as central to EDMD1 pathogenesis; leaves open CRISPR-based therapies for human muscle disease.
During myogenic differentiation, the Microtubule-Organizing Center (MTOC) is relocated to the nuclear envelope by a molecular platform including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins, A Kinase Anchoring Proteins (AKAP9 and AKAP6) and Pericentriolar Material 1 (PCM-1). Here, we show that emerin is required for centrosomal protein recruitment to the nuclear periphery of myonuclei and microtubule dynamics. In fact, in type 1 Emery-Dreifuss Muscular Dystrophy (EDMD1), loss of emerin was associated with altered pericentrin recruitment to the nuclear envelope, LINC protein impairment at the nuclear poles of myonuclei and microtubule organization defects. As a consequence, dynein, mitochondrial distribution and nuclear alignment along the longitudinal axis of the myotubes were altered in EDMD1 myotubes. Moreover, reduced levels of AKAP6 and PKA were detected at the nuclear periphery of EDMD1 myotubes, possibly contributing to an aberrant nuclear localization of the mechanosensing factor YAP. Upon rescue of emerin expression by CRISPR correction of mutated EMD gene: SUN1/2, pericentrin, AKAP6 and PKA were restored at the nuclear envelope and a correct YAP localization was observed in EDMD1 muscle cells. These results show that emerin is required for Nuclear Envelope-MTOC (NE-MTOC) organization in differentiating skeletal muscle cells and suggest that disruption of such complex is a key pathogenetic event in Emery-Dreifuss Muscular Dystrophy.
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Mattioli et al. (2026) studied Emery-Dreifuss Muscular Dystrophy (EDMD1). CRISPR correction of mutated EMD gene vs. Uncorrected EDMD1 cells was evaluated on Mislocalized nuclei in myotubes. CRISPR-mediated correction of the EMD gene in EDMD1 myotubes restored emerin expression, rescued centrosomal protein recruitment to the nuclear envelope, and decreased mislocalized nuclei from 48% to 35%.
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