Intellectual disability (ID) significantly limits both intellectual function and adaptive behavior and affects ~2% of the world's population, representing a major financial and societal burden. In developed countries, genetic mutation is the most common cause, and cannot be prevented. Nevertheless, since ID presents before the age of 18, while the brain is still developing, some types are likely treatable, with the right strategy. Still, >1000 genes are implicated in ID, so understanding the contribution of each, alone and in combination, is a major impediment. To tackle this problem, our strategy looks for anatomical, cellular and molecular points of convergence that are shared by IDs of different genetic and environmental origin. Lindsay will focus on an ID gene/protein interaction network that controls postnatal hippocampal development, with the view that disorder is well suited for clinical intervention. Under the parent grant, we recently made pioneering discoveries of mutations in the X- chromosome gene USP9X that cause ID (and also epilepsy and autism) in both males (missense mutations) and females (haploinsufficiency). USP9X encodes a deubiquitylating enzyme that opposes the ubiquitin-mediated proteasomal degradation of its substrates. Over 50 proteins are USP9X substrates and the ?USP9X interactome? influences major neurodevelopmental signaling pathways (e.g., Wnt, Notch, TGF?, mTOR, EGF, Hippo). Importantly, the USP9X interactome is highly enriched for proteins involved in IDs (e.g., DCX, CTNNB1, PRICKLE, among others). Critically, as USP9X regulates the stability and/or activity of its substrates, it sits at the apex of this ID gene/protein network. Finally, our unique brain-specific, knock-out mouse model reveals Usp9x influences postnatal hippocampal growth; and indeed, Usp9x-null mice have severe learning disabilities.
/Relevant to Public Health Epilepsy is a disabling disease that affects ~1% of the general population and requires long-term treatment. Most forms of epilepsy are inheritable, but for over 70% of patients, the underlying genetic basis for their condition remains unknown, impeding effective diagnosis and treatment. To develop new ways to diagnose and treat epilepsy, we aim to characterize genes and pathways not yet known to be involved, and to explore how these pathways might lead to new drug targets for epilepsy.
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| Yang, Jin; Bassuk, Alexander G; Merl-Pham, Juliane et al. (2016) Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors. Hum Mol Genet 25:4201-4210 |
| Zhang, Lijuan; Justus, Sally; Xu, Yu et al. (2016) Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa. Hum Mol Genet 25:4244-4255 |
| Ehaideb, Salleh N; Wignall, Elizabeth A; Kasuya, Junko et al. (2016) Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans. Ann Clin Transl Neurol 3:695-707 |
