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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

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hdl_144045.pdf (3.76 MB)
  (Published version)

Date

2024

Authors

McRae, H.M.
Leong, M.P.Y.
Bergamasco, M.I.
Garnham, A.L.
Hu, Y.
Corbett, M.A.
Whitehead, L.
El-Saafin, F.
Sheikh, B.N.
Wilcox, S.

Editors

Wang, H.

Advisors

Journal Title

Journal ISSN

Volume Title

Type:

Journal article

Citation

PLoS Genetics, 2024; 20(10):e1011428-1-e1011428-35

Statement of Responsibility

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

Conference Name

DOI

10.1371/journal.pgen.1011428

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.

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Dissertation Note

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Rights

© 2024 McRae et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Grant ID

http://purl.org/au-research/grants/nhmrc/1029481
 http://purl.org/au-research/grants/nhmrc/1084248
 http://purl.org/au-research/grants/nhmrc/1003435
 http://purl.org/au-research/grants/nhmrc/575512
 http://purl.org/au-research/grants/nhmrc/1081421
 http://purl.org/au-research/grants/nhmrc/1154970
 http://purl.org/au-research/grants/nhmrc/1155224
 http://purl.org/au-research/grants/nhmrc/1176789
 http://purl.org/au-research/grants/nhmrc/2025645

Published Version

https://doi.org/10.1371/journal.pgen.1011428

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Persistent link to this record

https://hdl.handle.net/2440/144045