Loss of DOT1L function disrupts neuronal transcription, animal behavior, and leads to a novel neurodevelopmental disorder

medRxiv [Preprint]. 2024 Nov 2:2024.10.31.24314716. doi: 10.1101/2024.10.31.24314716.

Abstract

Individuals with monoallelic pathogenic variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear. Here, we present a largely female cohort of 11 individuals with DOT1L variants with developmental delays and dysmorphic facial features. We found that DOT1L variants include missense variants clustered in the catalytic domain, frameshift, and stop-gain variants. We demonstrate that specific variants cause loss of methyltransferase activity and therefore sought to define the effects of decreased DOT1L function. Using RNA-sequencing of cultured neurons and single nucleus RNA-sequencing of mouse cortical tissue, we found that partial Dot1l depletion causes sex-specific transcriptional responses and disrupts transcription of synaptic genes. Further, Dot1l loss alters neuron branching and expression of synaptic proteins. Lastly using zebrafish and mouse models, we found behavioral disruptions that include sex-specific deficits in mice. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts transcription, neuron morphology, and behavior across multiple models and systems.

Publication types

  • Preprint