MBNL2 dysfunction in outer radial glial cells is associated with disrupted corticogenesis in congenital myotonic dystrophy [scRNA-Seq]

However, the role of MBNL in neurodevelopmental disorders associated with severe forms of DM1 remains poorly understood. We performed single-cell RNA sequencing using the 10x Genomics Chromium platform to investigate the cellular composition and transcriptomic alterations in forebrain organoids derived from an unaffected individual, a patient with congenital myotonic dystrophy (CDM) carrying approximately 2,000 CTG repeats or an isogenic control in which the pathogenic repeat expansion was removed.

Our analysis revealed that MBNL2, known to play a key role in the pathogenesis of myotonic dystrophy, is expressed in a subset of neural stem cells in mature forebrain organoids. We identified altered expression of genes involved in neuronal migration and axonal projection specifically in upper-layer cortical neurons of CDM organoids when compared with both the isogenic and the unaffected control. These findings suggest a role for MBNL2 during prenatal cortical development and highlight impaired differentiation of late-born neurons as a potential contributor to the neurodevelopmental abnormalities associated with CDM.