@article{1b8ab80127b34d7995f75599e139a14d,
title = "Characterization of a Mouse Model of B{\"o}rjeson-Forssman-Lehmann Syndrome",
abstract = "Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder B{\"o}rjeson-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. Cheng et al. generated a mouse model of B{\"o}rjeson-Forssman-Lehmann syndrome containing a patient-specific mutation of PHF6. PHF6 knockin mice display cognitive impairments, neuronal hyperexcitability, and seizure susceptibility. PHF6 promotes neurogenic and repressed synaptic genes in the cortex. This study advances understanding of the cellular and molecular underpinnings of BFLS.",
keywords = "PHF6, X-linked intellectual disability, gene expression, mouse models, neuronal excitability",
author = "Cheng Cheng and Deng, {Pan Yue} and Yoshiho Ikeuchi and Carla Yuede and Daofeng Li and Nicholas Rensing and Ju Huang and Dustin Baldridge and Maloney, {Susan E.} and Dougherty, {Joseph D.} and John Constantino and Arezu Jahani-Asl and Michael Wong and Wozniak, {David F.} and Ting Wang and Klyachko, {Vitaly A.} and Azad Bonni",
note = "Funding Information: The authors thank Chi Zhang for providing plasmids for the study, Anna Oldenberg for initial maintenance of the mouse line, and members of the Bonni laboratory for helpful discussions. This work was supported by NIH grants RO1NS088378 (to A.B.), RO1NS081972 (to V.A.K.), RO11HG007175 (to T.W.), and RF1MH117070-01 (to J.D.D.); Washington University Intellectual and Developmental Disabilities Research Center (IDDRC) NIH U54 HD087011; the Mouse Genetics core; the Hope Center Transgenic Vectors core; the Washington University Center for Cellular Imaging (WUCCI); and the Genome Technology Access Center (GTAC) at the Washington University School of Medicine. Funding Information: The authors thank Chi Zhang for providing plasmids for the study, Anna Oldenberg for initial maintenance of the mouse line, and members of the Bonni laboratory for helpful discussions. This work was supported by NIH grants RO1NS088378 (to A.B.), RO1NS081972 (to V.A.K.), RO11HG007175 (to T.W.), and RF1MH117070-01 (to J.D.D.); Washington University Intellectual and Developmental Disabilities Research Center (IDDRC) NIH U54 HD087011 ; the Mouse Genetics core ; the Hope Center Transgenic Vectors core ; the Washington University Center for Cellular Imaging (WUCCI); and the Genome Technology Access Center (GTAC) at the Washington University School of Medicine . Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = nov,
day = "6",
doi = "10.1016/j.celrep.2018.10.043",
language = "English",
volume = "25",
pages = "1404--1414.e6",
journal = "Cell Reports",
issn = "2211-1247",
number = "6",
}