The molecular impact of interferon regulatory factor 2 binding protein-like mutations in neurodevelopmental disorder with regression, abnormal movement, loss of speech, and seizures
| Author(s) | Bauer, Sarah Aiden | |
| Date Accessioned | 2025-04-14T16:53:56Z | |
| Date Available | 2025-04-14T16:53:56Z | |
| Publication Date | 2025 | |
| SWORD Update | 2025-04-14T04:01:32Z | |
| Abstract | One out of every six children globally will be diagnosed with a neurological disorder before age 14. Degenerative disorders specifically have a large impact as they can affect patients for decades following diagnosis. Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS) is an early-onset neurodegenerative disease that is characterized by de novo loss of function mutations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL). NEDAMSS patients experience regression and eventual loss of motor function/control, loss of speech, and seizures. As of 2024, there have only been 65 NEDAMSS patients identified. Like many other childhood neurodegenerative diseases, there is very little known about the mechanism underlying disease progression in these patients. As such, there are currently no treatment options for children with NEDAMSS outside of mediating the symptoms as they appear. ☐ IRF2BPL is a nuclear protein that is predominately expressed in neuronal tissue. Previous studies have demonstrated links between the E3 ubiquitin ligase activity of IRF2BPL and modulation of androgen receptor (AR) as well as WNT signaling. Our goal in this project is to characterize the molecular phenotype present in NEDAMSS patient cells. We observed an increase in the expression of IRF2BPL in healthy and NEDAMSS cells at both the protein and RNA levels and confirmed a method to reprogram fibroblasts into motor neurons. Using confocal imaging, we were able to establish that IRF2BPL is being mislocalized to the cytoplasm in cell lines carrying various mutations in IRF2BPL. The misregulation of WNT signaling in NEDMASS disease progression was further explained to involve the misregulation of LEF1 and JAGGED1. Additionally, a reduction of RAB25 seen in patient cells gives credence to the theory that AR signaling may play a role in developing the NEDAMSS phenotype. | |
| Advisor | Butchback, Matthew E. R. | |
| Degree | M.S. | |
| Department | University of Delaware, Department of Biological Sciences | |
| Unique Identifier | 1514958799 | |
| URL | https://udspace.udel.edu/handle/19716/36034 | |
| Language | en | |
| Publisher | University of Delaware | |
| URI | https://www.proquest.com/pqdtlocal1006271/dissertations-theses/molecular-impact-interferon-regulatory-factor-2/docview/3190089831/sem-2?accountid=10457 | |
| Keywords | Nuclear protein | |
| Keywords | Mutations | |
| Keywords | Neurodevelopmental disorder | |
| Keywords | Regression | |
| Keywords | Abnormal movements | |
| Keywords | Loss of speech | |
| Title | The molecular impact of interferon regulatory factor 2 binding protein-like mutations in neurodevelopmental disorder with regression, abnormal movement, loss of speech, and seizures | |
| Type | Thesis |