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Cell Rep. 2018 Nov 6;25(6):1404-1414.e6. doi: 10.1016/j.celrep.2018.10.043.

Characterization of a Mouse Model of Börjeson-Forssman-Lehmann Syndrome.

Author information

1
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA.
3
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine, 4515 McKinley Ave., St. Louis, MO 63108, USA.
6
Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis, MO 63108, USA.
7
Department of Genetics, Washington University School of Medicine, 4515 McKinley Ave., St. Louis, MO 63108, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63108, USA.
8
Department of Psychiatry, Division of Child Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
9
Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
10
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63108, USA.
11
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: bonni@wustl.edu.

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.

KEYWORDS:

PHF6; X-linked intellectual disability; gene expression; mouse models; neuronal excitability

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