A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation

Human genetics have defined a new neurodevelopmental syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes intellectual disability, autism, ADHD, obesity, and brain anomalies is unknown. Here, we developed a Myt1! haploinsufficient mouse model that develops obesity, white-matter thinning, and microcephaly, mimicking common clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1! gene-target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. Myt1! haploinsufficiency also results in behavioral anomalies, including hyperactivity, muscle weakness, and social alterations, with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.

Automated summary

A new neurodevelopmental syndrome caused by loss-of-function mutations in the MYT1L gene has been defined, with a haploinsufficient mouse model mimicking common clinical phenotypes. Disrupted gene expression and precocious neuronal differentiation were identified as mechanisms for microcephaly during brain development, while failure of transcriptional and chromatin maturation was discovered in adults, resulting in disruptions in baseline physiological properties of neurons. Behavioral anomalies, including hyperactivity, muscle weakness, and social alterations, were observed, with more severe phenotypes in males.