Cellular Models and High-Throughput Screening for Genetic Causality of Intellectual Disability

• Published in: Trends in molecular medicine 2021-03, Vol.27 (3), p.220-230
• Main Authors: Fell, Christopher W., Nagy, Vanja
• Format: Article
• Language: English
• Subjects: Animals; Cell Culture Techniques; CRISPR; High-Throughput Screening Assays - methods; high-throughput screens; Humans; intellectual disabilities; Intellectual Disability - genetics; Mice; neurodevelopmental disorder; Neurodevelopmental Disorders - genetics; Neurons - metabolism; RAC1; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; rho GTP-Binding Proteins; Rho GTPase
• ISSN: 1471-4914; 1471-499X
• DOI: 10.1016/j.molmed.2020.12.003

Intellectual disabilities (ID) are a type of neurodevelopmental disorder (NDD). They can have a genetic cause, including an emerging class of ID centring around Rho GTPases, such as Ras-related C3 botulinum toxin substrate 1 (RAC1). Guidelines for establishing genetic causality include the use of cellular models, which often have morphological aberrations, a long-standing hallmark of ID. Disease cellular models can facilitate high-throughput screening (HTS) of chemical or genetic perturbations, which can provide translatable biological insight. Here, we discuss a class of IDs centring around RAC1. We review novel and established cellular models of ID, including mouse and human primary cells and reprogrammed or induced neurons. Finally, we review progress and remaining challenges in the adoption of HTS methodologies by the community studying neurological disorders. Next-generation sequencing of patients with ID continues to identify genes important to neuronal development.Network analysis of ID genes shows functional convergence on molecular hubs, including the Rho GTPase RAC1. Functional variants in RAC1 and regulators of RAC1 activity (including HACE1 and TRIO) cause ID with variable symptoms.Inaccessibility of primary material from patients with ID has motivated the development of alternative primary (murine neurons and fibroblasts) and reprogrammed [induced pluripotent stem cells, induced neurons (iNs), and blood iNs] cellular models, each with unique advantages and disadvantages.Adoption of HTS methodologies into neuroscience has been slow, but recent cellular model advances address many limitations.