AI Article Synopsis
- Mutations in the PHF6 gene are linked to Börjeson-Forssman-Lehmann syndrome (BFLS), a disorder causing intellectual disabilities, but how these mutations lead to the disease is not well understood.
- Researchers created a mouse model with a specific mutation (C99F) in PHF6 using CRISPR technology, which showed cognitive and behavioral deficits along with an increased risk of seizures.
- Further studies revealed that PHF6 plays a crucial role in regulating gene expression related to neurogenesis and synaptic functions, highlighting potential mechanisms involved in the development of neurodevelopmental disorders like BFLS.
Article Abstract
Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS), but the pathogenesis of BFLS remains poorly understood. Here, we report a mouse model of BFLS, generated using a CRISPR-Cas9 approach, in which cysteine 99 within the PHD domain of PHF6 is replaced with phenylalanine (C99F). Mice harboring the patient-specific C99F mutation display deficits in cognitive functions, emotionality, and social behavior, as well as reduced threshold to seizures. Electrophysiological studies reveal that the intrinsic excitability of entorhinal cortical stellate neurons is increased in PHF6 C99F mice. Transcriptomic analysis of the cerebral cortex in C99F knockin mice and PHF6 knockout mice show that PHF6 promotes the expression of neurogenic genes and represses synaptic genes. PHF6-regulated genes are also overrepresented in gene signatures and modules that are deregulated in neurodevelopmental disorders of cognition. Our findings advance our understanding of the mechanisms underlying BFLS pathogenesis.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261530 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2018.10.043 | DOI Listing |
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