Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia.

BACKGROUND: Similar to some monogenic forms of dystonia, levodopa-induced dyskinesia is a hyperkinetic movement disorder with abnormal nigrostriatal dopaminergic neurotransmission. Molecularly, it is characterized by hyper-induction of phosphorylation of extracellular signal-related kinase in response to dopamine in medium spiny neurons of the direct pathway. OBJECTIVES: The objective of this study was to determine if mouse models of monogenic dystonia exhibit molecular features of levodopa-induced dyskinesia. METHODS: Western blotting and quantitative immunofluorescence was used to assay baseline and/or dopamine-induced levels of the phosphorylated kinase in the striatum in mouse models of DYT1, DYT6, and DYT25 expressing a reporter in dopamine D1 receptor-expressing projection neurons. Cyclic adenosine monophosphate (cAMP) immunoassay and adenylyl cyclase activity assays were also performed. RESULTS: In DYT1 and DYT6 models, blocking dopamine reuptake with cocaine leads to enhanced extracellular signal-related kinase phosphorylation in dorsomedial striatal medium spiny neurons in the direct pathway, which is abolished by pretreatment with the N-methyl-d-aspartate antagonist MK-801. Phosphorylation is decreased in a model of DYT25. Levels of basal and stimulated cAMP and adenylyl cyclase activity were normal in the DYT1 and DYT6 mice and decreased in the DYT25 mice. Oxotremorine induced increased abnormal movements in the DYT1 knock-in mice. CONCLUSIONS: The increased dopamine induction of extracellular signal-related kinase phosphorylation in 2 genetic types of dystonia, similar to what occurs in levodopa-induced dyskinesia, and its decrease in a third, suggests that abnormal signal transduction in response to dopamine in the postsynaptic nigrostriatal pathway might be a point of convergence for dystonia and other hyperkinetic movement disorders, potentially offering common therapeutic targets. © 2021 International Parkinson and Movement Disorder Society.