Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.

The TATA-box binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked Dystonia-Parkinsonism, a neurodegenerative disorder. However, this field has suffered from the lack of a genetic mouse model of TAF1 disease to explore mammalian mechanism and treatments. Here, we generated and validated a conditional cre-lox allele, and the first ubiquitous Taf1 knock-out mouse. We discovered that Taf1 deletion in males was embryonically lethal, which may explain why no human null-variants have been identified. In the brains of Taf1 heterozygous females, no differences were found in gross structure, overall expression, and protein localization, suggesting extreme skewed X-inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting a small subset of neurons has been negatively impacted by Taf1 loss. Finally, this new mouse may be a future platform for the development of TAF1 disease therapeutics.