*** IBB - CNR *** Institute of Biostructure and Bioimaging, CNR, Napoli, Italy. Dipartimento di Biotecnologie e Scienze della Vita, Universita degli studi dell'Insubria, via J.H. Dunant 3, 21110, Varese, Italy. Department of Medical Biotechnology and Translational Medicine, Universita degli Studi di Milano, Milan, Italy. Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy. CNR- Neuroscience Institute, Milan, Italy.
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About 90% of Congenital Central Hypoventilation Syndrome (CCHS) patients show poly-alanine triplet expansions in the coding region of transcription factor PHOX2B, which renders this protein an intriguing target to understand the insurgence of this syndrome and for the design of a novel therapeutical approach. Consistently with the role of PHOX2B as a transcriptional regulator, it is reasonable that a general transcriptional dysregulation caused by the poly-alanine expansion might represent an important mechanism underlying CCHS pathogenesis. Therefore, this study focused on the biochemical characterization of different PHOX2B variants, such as a variant containing the correct C-terminal (20-alanines) stretch, one of the most frequent poly-alanine expansions (+7-alanines), and a variant lacking the complete alanine stretch (0-alanines). Comparison of the different variants by a multidisciplinary approach based on different methodologies (including circular dichroism, spectrofluorimetry, light scattering and Atomic Force Microscopy studies) highlighted the propensity to aggregate for the PHOX2B variant containing the poly-alanine expansion (+7-alanines), especially in the presence of DNA, while the 0-alanines variant resembled the protein with the correct poly-alanine length. Moreover, and unexpectedly, the formation of fibrils was revealed only for the pathological variant, suggesting a plausible role of such fibrils in the insurgence of CCHS. This article is protected by copyright. All rights reserved.<br>