Heterozygosity for Nuclear Factor One X in mice models features of Malan syndrome

Sabrina Oishi; Danyon Harkins; Nyoman D Kurniawan; Maria Kasherman; Lachlan Harris; Oressia Zalucki; Richard M Gronostajski; Thomas H J Burne; Michael Piper

doi:10.1016/j.ebiom.2018.11.044

Heterozygosity for Nuclear Factor One X in mice models features of Malan syndrome

EBioMedicine. 2019 Jan:39:388-400. doi: 10.1016/j.ebiom.2018.11.044. Epub 2018 Nov 29.

Authors

Sabrina Oishi¹, Danyon Harkins¹, Nyoman D Kurniawan², Maria Kasherman³, Lachlan Harris⁴, Oressia Zalucki¹, Richard M Gronostajski⁵, Thomas H J Burne⁶, Michael Piper⁷

Affiliations

¹ The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
² The Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia.
³ The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
⁴ The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; The Francis Crick Institute, 1 Midland Road, King's Cross, London, United Kingdom.
⁵ Department of Biochemistry, Program in Genetics, Genomics and Bioinformatics, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.
⁶ The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Brisbane, QLD 4076, Australia.
⁷ The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: m.piper@uq.edu.au.

Abstract

Background: Nuclear Factor One X (NFIX) haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to the enlarged head circumference and intellectual disability in these patients remains undefined.

Methods: Here, we used Nfix heterozygous mice as a model to investigate these aspects of Malan syndrome. Volumetric magnetic resonance imaging (MRI) was used to calculate the volumes of 20 brain sub regions. Diffusion tensor MRI was used to perform tractography-based analyses of the corpus callosum, hippocampal commissure, and anterior commissure, as well as structural connectome mapping of the whole brain. Immunohistochemistry examined the neocortical cellular populations. Two behavioral assays were performed, including the active place avoidance task to assess spatial navigation and learning and memory function, and the 3-chambered sociability task to examine social behaviour.

Findings: Adult Nfix^+/- mice exhibit significantly increased brain volume (megalencephaly) compared to wildtypes, with the cerebral cortex showing the highest increase. Moreover, all three forebrain commissures, in particular the anterior commissure, revealed significantly reduced fractional anisotropy, axial and radial diffusivity, and tract density intensity. Structural connectome analyses revealed aberrant connectivity between many crucial brain regions. Finally, Nfix^+/- mice exhibit behavioral deficits that model intellectual disability.

Interpretation: Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit. FUND: Australian Research Council (ARC) Discovery Project Grants, ARC Fellowship, NYSTEM and Australian Postgraduate Fellowships.

Keywords: Intellectual disability; Macrocephaly; Malan syndrome; NFIX.

MeSH terms

Animals
Cerebral Cortex / diagnostic imaging*
Connectome
Disease Models, Animal
Female
Haploinsufficiency*
Humans
Intellectual Disability / diagnostic imaging
Intellectual Disability / genetics*
Intellectual Disability / psychology
Magnetic Resonance Imaging
Male
Megalencephaly / diagnostic imaging
Megalencephaly / genetics*
Megalencephaly / psychology
Mice
NFI Transcription Factors / genetics*
Organ Size
Spatial Learning

Substances

NFI Transcription Factors
Nfix protein, mouse