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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Brain / pathology
  • Carrier Proteins / genetics
  • Cognition
  • Disease Models, Animal
  • Disease Susceptibility
  • Emotions
  • Epilepsy / genetics
  • Epilepsy / pathology*
  • Face / abnormalities*
  • Face / pathology
  • Fingers / abnormalities*
  • Fingers / pathology
  • Gene Expression Regulation
  • Growth Disorders / genetics
  • Growth Disorders / pathology*
  • Hypogonadism / genetics
  • Hypogonadism / pathology*
  • Interpersonal Relations
  • Male
  • Mental Retardation, X-Linked / genetics
  • Mental Retardation, X-Linked / pathology*
  • Mice
  • Mice, Mutant Strains
  • Neurons / metabolism
  • Neurons / pathology
  • Obesity / genetics
  • Obesity / pathology*
  • Repressor Proteins
  • Seizures / pathology
  • Synapses / metabolism
  • Transcription, Genetic


  • Carrier Proteins
  • PHF6 protein, human
  • Repressor Proteins

Supplementary concepts

  • Borjeson-Forssman-Lehmann syndrome