RESUMEN
De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of irf2bpl in zebrafish also causes neurological defects with an associated increase in wnt1 transcription and downstream signaling. WNT1 is also increased in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes. Last, IRF2BPL and the Wnt antagonist, CKIα, physically and genetically interact, showing that IRF2BPL and CkIα antagonize Wnt transcription and signaling.
Asunto(s)
Proteínas de Drosophila , Animales , Proteínas Portadoras/metabolismo , Niño , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Humanos , Factor 2 Regulador del Interferón/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/genética , Vía de Señalización Wnt , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
One of the greatest challenges in the bioinformatic analysis of human sequencing data is identifying which variants are pathogenic. Numerous databases and tools have been generated to address this difficulty. However, these many useful data and tools are broadly dispersed, requiring users to search for their variants of interest through human genetic databases, variant function prediction tools, and model organism databases. To solve this problem, we collected data and observed workflows of human geneticists, clinicians, and model organism researchers to carefully select and display valuable information that facilitates the evaluation of whether a variant is likely to be pathogenic. This program, Model organism Aggregated Resources for Rare Variant ExpLoration (MARRVEL) v1.2, allows users to collect relevant data from 27 public sources for further efficient bioinformatic analysis of the pathogenicity of human variants. © 2019 by John Wiley & Sons, Inc.
