redwan huq baylor college of medicine email

Results Humans Carrying Pathogenic Variants in UPF2 Exhibit Speech and Language Impairments and Impaired NMD Finally, Upf2 fb-KO mice recapitulate the human UPF2 phenotype by showing vocal communication problems that were rescued by Food and Drug Administration (FDA)-approved agents that reduce brain inflammation. In addition, we identified three individuals with novel variants in UPF2 who exhibited speech deficits, implicating Upf2-mediated control of NMD as a new pathway involved in speech and language. Integrating multiple approaches such as transcriptomics, flow cytometry, immunohistochemistry, pharmacology, and behavior, we provide causal evidence that over-activation of the immune response contributes to the deficits in long-term memory (LTM), synaptic plasticity, and social behaviors caused by loss of Upf2 in mice. We also sought to identify the mechanism by which loss of Upf2-dependent NMD leads to these neurodevelopmental impairments in mice. Similar to individuals with deletions encompassing the UPF2 locus, we found that Upf2 forebrain-specific knockout (Upf2 fb-KO) mice exhibit learning and memory impairments and display social deficits and behavioral inflexibility. To address this, we inhibited NMD in vivo by conditionally removing Upf2 in the murine forebrain.

Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Here we identified novel protein-coding UPF2 ( UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. In humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability.

Redwan huq baylor college of medicine email