Irf2bpl, or Interferon regulatory factor 2 binding protein-like, encodes a member of the IRF2BP family of transcriptional regulators. Its exact biological function remains somewhat obscure, but research indicates its importance in the nervous system [1,2,3,4,5,6,7,8,9]. Bioinformatics signatures suggest it is intolerant to variation, hinting at its crucial role in biological processes. Genetic models, such as the fruit-fly ortholog pits, have been valuable in studying its function [1].

In humans, damaging heterozygous variants in Irf2bpl are associated with a range of neurological phenotypes. Nonsense variants often lead to severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and lack of coordination, while missense variants may result in global developmental delay and seizures with a relatively milder phenotype [1]. In fruit-flies, complete loss of pits is lethal early in development, and partial knockdown in neurons causes neurodegeneration, highlighting its requirement for proper neuronal function and maintenance [1]. Moreover, in Drosophila, overexpression of either Irf2bpl or Pits represses Wnt transcription, and neuronal depletion of Pits leads to increased wingless (wg) levels in the brain, axonal loss, which can be mitigated by inhibiting Wg signaling. Loss of irf2bpl in zebrafish also causes neurological defects with increased wnt1 transcription [7].

In conclusion, Irf2bpl is essential for proper neuronal function and maintenance, as revealed through model-based research. Variants in this gene are associated with various neurological disorders, including developmental and epileptic encephalopathy, progressive myoclonus epilepsy, and late-onset ataxia. Studies using model organisms like flies and zebrafish have provided valuable insights into the role of Irf2bpl in the nervous system and the underlying mechanisms of these neurological diseases [1,3,5,6,7].

References:

1. Marcogliese, Paul C, Shashi, Vandana, Spillmann, Rebecca C, Bellen, Hugo J, Pena, Loren D M. 2018. IRF2BPL Is Associated with Neurological Phenotypes. In American journal of human genetics, 103, 245-260. doi:10.1016/j.ajhg.2018.07.006. https://pubmed.ncbi.nlm.nih.gov/30057031/

2. Shelkowitz, Emily, Singh, Jasleen K, Larson, Austin, Elias, Ellen R. 2019. IRF2BPL gene mutation: Expanding on neurologic phenotypes. In American journal of medical genetics. Part A, 179, 2263-2271. doi:10.1002/ajmg.a.61328. https://pubmed.ncbi.nlm.nih.gov/31432588/

3. Heide, Solveig, Davoine, Claire-Sophie, Cunha, Paulina, Brice, Alexis, Durr, Alexandra. 2023. IRF2BPL Causes Mild Intellectual Disability Followed by Late-Onset Ataxia. In Neurology. Genetics, 9, e200096. doi:10.1212/NXG.0000000000200096. https://pubmed.ncbi.nlm.nih.gov/38235039/

4. Sinha Ray, Shrestha, Dutta, Debdeep, Dennys, Cassandra, Marcogliese, Paul C, Meyer, Kathrin C. . Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy. In Cell reports, 41, 111751. doi:10.1016/j.celrep.2022.111751. https://pubmed.ncbi.nlm.nih.gov/36476864/

5. Costa, Cinzia, Oliver, Karen L, Calvello, Carmen, Berkovic, Samuel F, Prontera, Paolo. 2023. IRF2BPL: A new genotype for progressive myoclonus epilepsies. In Epilepsia, 64, e164-e169. doi:10.1111/epi.17557. https://pubmed.ncbi.nlm.nih.gov/36810721/

6. Gardella, Elena, Michelucci, Roberto, Christensen, Hanne M, Møller, Rikke S, Rubboli, Guido. 2023. IRF2BPL as a novel causative gene for progressive myoclonus epilepsy. In Epilepsia, 64, e170-e176. doi:10.1111/epi.17634. https://pubmed.ncbi.nlm.nih.gov/37114479/

7. Marcogliese, Paul C, Dutta, Debdeep, Ray, Shrestha Sinha, Yeo, Nan Cher, Bellen, Hugo J. 2022. Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling. In Science advances, 8, eabl5613. doi:10.1126/sciadv.abl5613. https://pubmed.ncbi.nlm.nih.gov/35044823/

8. Yang, Fei, Li, Hui, Dai, Yi, Zhang, Ran, Zhang, Jiang-Tao. 2023. IRF2BPL gene variants with dystonia: one new Chinese case report. In BMC neurology, 23, 32. doi:10.1186/s12883-023-03077-x. https://pubmed.ncbi.nlm.nih.gov/36670390/

9. Bauersachs, Daniel, Bomholtz, Louise, Del Rey Mateos, Sara, Kühn, Ralf, Lisowski, Pawel. 2024. Novel human neurodevelopmental and neurodegenerative disease associated with IRF2BPL gene variants-mechanisms and therapeutic avenues. In Frontiers in neuroscience, 18, 1426177. doi:10.3389/fnins.2024.1426177. https://pubmed.ncbi.nlm.nih.gov/38903604/