Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Evolutionary Analysis of Rett Syndrome-Causing Proteins and Their Pathogenic Missense Point Mutations: Structural Order–Disorder, Post-Translational Modifications, Evolutionary Rates, and Interacting Proteins

Version 1 : Received: 29 June 2019 / Approved: 1 July 2019 / Online: 1 July 2019 (11:59:56 CEST)

A peer-reviewed article of this Preprint also exists.


Rett syndrome (RTT) is mainly caused by mutations in methyl CpG-binding protein 2, cyclin-dependent kinase-like 5, or forkhead box protein G1. These RTT-causing proteins harbor an intrinsically disordered region (IDR) whose conformation exhibits spatiotemporal heterogeneity, which not only confer versatility to the protein, but also implicates them in diseases. The IDR generally evolves more rapidly than an ordered structure. In this study, we examined the relationship between pathogenic RTT-associated point mutations in RTT-causing proteins and the evolutionary dynamics of sequence features including structural order–disorder, phosphorylation sites, and evolutionary rates. We also analyzed the molecular properties and evolution of proteins that interact with RTT-causing proteins in terms of phylogenetic profiles, tissue specificity, subcellular localization, expression level, and functions. The results indicate that constrained IDRs may function by forming contacts with other regions in the protein sequence causing pathogenic missense mutations likely to arise in the rapidly evolving IDR and affect molecular networks, leading to disease. The results also provide novel insights into the genetic basis for RTT and the evolution of the neocortex in higher vertebrates.


Rett Syndrome; intrinsically disordered region; phylogenetic profile analysis; post-transcriptional modification; methyl-CpG-binding protein 2; cyclin-dependent kinase-like 5; forkhead box protein G1


Biology and Life Sciences, Biochemistry and Molecular Biology

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