Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain. Author summary: The Börjeson-Forssman-Lehmann Syndrome (BFLS) is an intellectual disability and endocrine disorder. Mutations in the plant homeodomain finger 6 gene (PHF6) cause the disorder. We show here that a subset of BFLS patients lack PHF6 and report the effects of loss of PHF6 in an animal model with complete loss of PHF6 from conception. The cerebral cortex is the site of higher brain functions, including cognition and decision-making. We report here the effects of lack of PHF6 on the developing brain, cerebral cortex and neuronal cells isolated from this structure. Since PHF6 associates with the genetic material in the cell nucleus and has been proposed to regulate gene activity, we also report the effects of lack of PHF6 on gene expression in the cerebral cortex and purified neuronal cells. We observed that loss of PHF6 results in the dysregulation of neuronal development and differentiation genes, including genes involved in disorders such as Parkinson's disease, epilepsy, neuroblastoma, attention deficit disorder, autism and schizophrenia. Lastly, we report that mice lacking PHF6 mirror BFLS patients in that they also suffer from spontaneous epileptic seizures. Our mouse models and findings will be useful to further investigate BFLS neuronal function and other aspects of the disorder in the adult. [ABSTRACT FROM AUTHOR]