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
- Author(s)
- McRae, HM; Leong, MPY; Bergamasco, MI; Garnham, AL; Hu, Y; Corbett, MA; Whitehead, L; El-Saafin, F; Sheikh, BN; Wilcox, S; Hannan, AJ; Gécz, J; Smyth, GK; Thomas, T; Voss, AK;
- Details
- Publication Year 2024-10,Volume 20,Issue #10,Page e1011428
- Journal Title
- PLoS Genetics
- Abstract
- 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.
- Publisher
- PLOS
- Keywords
- Animals; Mice; *Disease Models, Animal; *Seizures/genetics/metabolism; *Mental Retardation, X-Linked/genetics/pathology; Humans; *Repressor Proteins/genetics/metabolism; Female; Male; Face/abnormalities; Intellectual Disability/genetics; Cerebral Cortex/metabolism/pathology; Hypogonadism/genetics/pathology/metabolism; Vestibular Diseases/genetics/pathology; Calcinosis/genetics/pathology/metabolism; Neural Stem Cells/metabolism; Mice, Knockout; Transcription, Genetic; Epilepsy; Fingers/abnormalities; Growth Disorders; Obesity
- Research Division(s)
- Bioinformatics; Advanced Technology And Biology; Epigenetics And Development
- PubMed ID
- 39405291
- Publisher's Version
- https://doi.org/10.1371/journal.pgen.1011428
- Open Access at Publisher's Site
https://doi.org/10.1371/journal.pgen.1011428- Terms of Use/Rights Notice
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Creation Date: 2024-10-25 10:15:31
Last Modified: 2024-10-25 10:41:05