Autism- and intellectual disability-associated MYT1L mutation alters human cortical interneuron differentiation, maturation, and physiology

• DOI: 10.1016/j.stemcr.2025.102421
• Publication Date: 2025-02-27T15:31:44Z
• Authors: Ramachandran Prak...; Julianna Determan; Gareth Chapman; Mishka Narasimhan; Renata Shen; Maamoon Saleh; Komal Kaushik; Paul Gontarz; Kesavan Meganathan; Bilal Hakim; Bo Zhang; James E. Huettner; Kristen L. Kroll
• Keywords: Interneuron; Brain Development

SUMMARYMYT1L is a neuronal transcription factor highly expressed in the developing and adult brain. While pathogenicMYT1Lmutation causes neurodevelopmental disorders, these have not been characterized in human models of neurodevelopment. Here, we defined the consequences of pathogenicMYT1Lmutation in human pluripotent stem cell-derived cortical interneurons. During differentiation, mutation reduced MYT1L expression and increased progenitor cell cycle exit and neuronal differentiation and synapse-related gene expression, morphological complexity, and synaptic puncta formation. Conversely, interneuron maturation was compromised, while variant neurons exhibited altered sodium and potassium channel activity and reduced function in electrophysiological analyses. CRISPRi-based knockdown similarly impaired interneuron differentiation and maturation, supporting loss of function-based effects. We further defined MYT1L genome-wide occupancy in interneurons and related this to the transcriptomic dysregulation resulting fromMYT1Lmutation, to identify direct targets that could mediate these phenotypic consequences. Together, this work delineates contributors to the etiology of neurodevelopmental disorders resulting fromMYT1Lmutation.