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Philip M. Boone

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Open access Jul 2026

CRISPR-engineered deletion of POGZ alters transcription factor binding at promoters of genes involved in synaptic signaling

Summary One of the seminal discoveries from genetic studies of autism spectrum disorder and related neurodevelopmental disorders (NDDs) has been that loss-of-function (LoF) mutations in genes that impact transcriptional regulation confer substantial liability to NDDs. Haploinsufficiency of the epigenetic regulator POGZ represents one of the strongest such associations; however, little is known about the mechanisms by which POGZ LoF alters early neuronal development. Here, we created an allelic series of CRISPR-engineered human induced pluripotent stem cell (hiPSC) clones harboring mono- and bi-allelic POGZ deletions. In hiPSC-derived neural stem cells (NSCs) and Neurogenin-2-induced neurons (iNs), POGZ LoF altered the expression of genes associated with synaptic and intracellular signaling and extracellular matrix organization. Our multiomics profiling also showed altered footprinting of critical transcription factors (e.g., activator protein 1 complexes) that were enriched at promoters of differentially expressed genes associated with synaptic function. To further interrogate the shared molecular changes associated with NDDs, we compared our results to deletions of the transcription factor MEF2C and the sodium channel gene SCN2A that we generated in these same isogenic iNs. These analyses revealed strong enrichment of extracellular matrix and intracellular signaling disruption associated with POGZ and MEF2C deletion, whereas POGZ and SCN2A haploinsufficiency exhibited shared transcriptional effects on gene modules enriched for NDD-associated genes with opposing regulatory effects. Notably, we also observed alterations to synaptic firing rate and neurite extension with bi-allelic deletions. These shared molecular consequences suggest key points of convergence that connect gene regulation to neuronal function in the etiology of neurodevelopmental pathologies.

M. Moyses-Oliveira, Yating Liu, Serkan Erdin et al. · 1 citation
Open access Jul 2026

Further characterization of the BRSK2-associated neurodevelopmental disorder.

Variants in BRSK2, encoding brain specific kinase-2, have recently been associated with an autosomal dominant neurodevelopmental disorder (NDD). We have assembled 52 cases with heterozygous BRSK2 variants and variable neurodevelopmental phenotypes with frequent neuropsychiatric and behavioral symptoms. The variant spectrum included 15 different truncating variants, seven (potential) splice variants, three structural variants, and 12 different missense variants. Of the missense variants, seven were in the kinase domain, and the others in the UBA and the KA1 domain or outside domains. Variants occurred de novo in 19 cases and were inherited in 18. We utilized Drosophila melanogaster as a model and assessed viability and performed climbing and bang sensitivity assays upon knockdown of the fly orthologue sff or upon overexpression of wildtype or mutant human BRSK2. Pan-neuronal knockdown of sff resulted in impaired locomotor behavior and seizure susceptibility. Ubiquitous or pan-neuronal overexpression of human wildtype BRSK2 in Drosophila resulted in lethality or locomotor impairment, respectively, indicating toxicity. Overexpressing mutant BRSK2 did not or incompletely affect viability and locomotor behavior for six of seven tested kinase domain missense variants and one KA1 domain variant, indicating a (partial) loss-of-function effect. Interestingly, overexpressing BRSK2 with the remaining missense variant from the kinase domain and the two most C-terminal missense variants resulted in possible gain of function. Our findings further delineate the clinical and molecular spectrum of BRSK2-associated NDD and provide further insights into the role of BRSK2/sff in nervous system function and dysfunction.

Palak Singhal, Tzung-Chien Hsieh, Nadja Ehmke et al. · 0 citations