USP9X Gene Essential to Early Human Brain Development, University of Adelaide Study Finds

New research from the University of Adelaide confirms that the gene USP9X, long linked to intellectual disability, plays a crucial role during the earliest stages of human brain development.

Researchers at the University of Adelaide have studied USP9X for more than a decade, and recent work has clarified how this gene contributes to the formation and wiring of the developing brain. An international research team led by the Robinson Research Institute at the University of Adelaide published their findings in the American Journal of Human Genetics, showing that mutations in USP9X are associated with intellectual disability and disrupt normal neuronal function.

The study, which appears under the title “Mutations in USP9X Are Associated with X-Linked Intellectual Disability and Disrupt Neuronal Cell Migration and Growth,” links changes in USP9X to altered neuron generation and impairment of neuronal migration and growth. These disruptions can interfere with the establishment of the brain’s foundational network of nerve cells during embryonic development.

Speaking during Brain Awareness Week, senior co-author Dr Lachlan Jolly of the University of Adelaide’s Neurogenetics Research Program emphasized the gene’s importance in early neurodevelopment. “Not surprisingly, disorders that change the brain’s network of cells — such as intellectual disability, epilepsy and autism — are complex and difficult to treat,” Dr Jolly said. “By studying patients with severe learning and memory challenges, we identified USP9X as a gene that helps create the brain’s base network of nerve cells. USP9X controls both the initial generation of those cells from stem cells and their ability to connect and form proper neural circuits.”

Mutations in USP9X, which can be inherited from one generation to the next, have been shown to cause disruptions to normal brain cell functioning. This image is not connected to the research and is for illustrative purposes. It is a diagram showing the brain and major nerves of a 6 week old human fetus. Credit Kurzon.

Understanding the role of USP9X helps illuminate fundamental questions about how the brain is built. During the embryonic stage, the basic framework for the brain’s complex network of neurons is established. Genes that control cell proliferation, differentiation and migration are therefore essential to healthy brain formation; mutations in those genes can alter neural architecture in ways that underlie intellectual disability and related conditions.

The research team’s work delves into how USP9X influences both the production of neurons from precursor stem cells and the subsequent steps by which those neurons migrate, extend processes, and form synaptic connections. When typical USP9X function is disrupted by mutation, those processes can be impaired, which helps explain the clinical observations of learning and developmental difficulties in affected individuals.

While translating these basic discoveries into therapies will take time, the findings provide a clearer genetic and cellular basis for a subset of intellectual disabilities. Dr Jolly noted that gaining a better molecular-level understanding of genes such as USP9X creates opportunities to study brain disorders more deeply than before and may ultimately point toward targeted strategies for intervention or supportive therapies.

Notes about this genetics and brain development research

The research was supported by the National Health and Medical Research Council (NHMRC) and the Women’s and Children’s Hospital Foundation.

Contact: Dr Lachlan Jolly – University of Adelaide

Source: University of Adelaide press release; study published in American Journal of Human Genetics, March 2014. Original research DOI: 10.1016/j.ajhg.2014.02.004. The published work is titled “Mutations in USP9X Are Associated with X-Linked Intellectual Disability and Disrupt Neuronal Cell Migration and Growth” and lists Claire C. Homan, Raman Kumar, Lam Son Nguyen, Eric Haan, F. Lucy Raymond, Fatima Abidi, Martine Raynaud, Charles E. Schwartz, Stephen A. Wood, Jozef Gecz and Lachlan A. Jolly among the authors.

By linking inherited mutations in USP9X to specific disruptions in neuron generation, migration and growth, this study advances understanding of how genetic variation can shape early brain development and lead to neurodevelopmental disorders. Continued research into the pathways regulated by USP9X will be important for identifying how these processes might be supported or corrected in the future.