Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth

Am J Hum Genet. 2014 Mar 6;94(3):470-8. doi: 10.1016/j.ajhg.2014.02.004.

Claire C Homan ¹, Raman Kumar ², Lam Son Nguyen ³, Eric Haan ⁴, F Lucy Raymond ⁵, Fatima Abidi ⁶, Martine Raynaud ⁷, Charles E Schwartz ⁶, Stephen A Wood ⁸, Jozef Gecz ⁹, Lachlan A Jolly ¹⁰

Affiliations

1 School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia.
2 Women's and Children's Health Research Institute, North Adelaide, SA 5006, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia.
3 School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia.
4 School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia; South Australian Clinical Genetics Service, SA Pathology at Women's and Children's Hospital, North Adelaide, SA 5006, Australia.
5 Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
6 J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC 29646, USA.
7 CHRU de Tours, Service de Génétique, Tours 37000, France; Inserm U930, UMR Imagerie et Cerveau, Tours 37000, France.
8 Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
9 School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia; Women's and Children's Health Research Institute, North Adelaide, SA 5006, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia; Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: jozef.gecz@adelaide.edu.au.
10 School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia; Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: lachlan.jolly@adelaide.edu.au.

PMID: 24607389 DOI: 10.1016/j.ajhg.2014.02.004

Abstract

With a wealth of disease-associated DNA variants being recently reported, the challenges of providing their functional characterization are mounting. Previously, as part of a large systematic resequencing of the X chromosome in 208 unrelated families with nonsyndromic X-linked intellectual disability, we identified three unique variants (two missense and one protein truncating) in USP9X. To assess the functional significance of these variants, we took advantage of the Usp9x knockout mouse we generated. Loss of Usp9x causes reduction in both axonal growth and neuronal cell migration. Although overexpression of wild-type human USP9X rescued these defects, all three USP9X variants failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration. Interestingly, in one of these families, the proband was subsequently identified to have a microdeletion encompassing ARID1B, a known ID gene. Given our findings it is plausible that loss of function of both genes contributes to the individual's phenotype. This case highlights the complexity of the interpretations of genetic findings from genome-wide investigations. We also performed proteomics analysis of neurons from both the wild-type and Usp9x knockout embryos and identified disruption of the Cytoskeleton as the main underlying consequence of the loss of Usp9x. Detailed clinical assessment of all three families with USP9X variants identified hypotonia and behavioral and morphological defects as common features in addition to ID. Together our data support involvement of all three USP9X variants in ID in these families and provide likely cellular and molecular mechanisms involved.

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