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

• DOI: 10.1371/journal.pgen.1011428
• Publication Date: 2024-10-15T17:30:56Z
• Authors: Helen M. McRae; Melody P. Y. Leong; Maria I. Bergamasco; Alexandra L. Garnham; Yifang Hu; Mark A. Corbett; Lachlan Whitehead; Farrah El-Saafin; Bilal N. Sheikh; Stephen Wilcox; Anthony J. Hannan; Jozef Gécz; Gordon K. Smyth; Tim Thomas; Anne K. Voss
• Keywords: Male; Cerebral Cortex; Mice, Knockout; Transcription, Genetic; Hypogonadism; Calcinosis; Fingers; Repressor Proteins; Mice; Disease Models, Animal; Neural Stem Cells; Vestibular Diseases; Seizures; Face; Intellectual Disability; Mental Retardation, X-Linked; Animals; Humans; Female; Obesity; Research Article

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 the role in vivo development mammalian nervous system required to advance our knowledge how mutations cause BFLS. Here, we show that protein levels are greatly reduced cells derived from a subset patients with We report phenotypic, anatomical, cellular molecular characterization brain males females two mouse models BFLS, namely loss Phf6 germline system-specific deletion . resulted spontaneous seizures occurring via neural intrinsic mechanism. Histological morphological analysis revealed significant enlargement lateral ventricles adult -deficient mice, while other structures cortical lamination were normal. deficient precursor showed capacity for self-renewal increased differentiation into neurons. neurons commenced neuronal activity prematurely suggesting precocious maturation. foetal cortex isolated predominantly upregulation genes, including Reln , Nr4a2 Slc12a5 Phip ZIC family transcription factor involved function, providing insight effects developing brain.