**In Silico Study of Rett Syndrome Treatment-Related Genes,** *MECP2***,** *CDKL5***, and** *FOXG1***, by Evolutionary Classification and Disordered Region Assessment**

**Muhamad Fahmi 1, Gen Yasui 1, Kaito Seki 1, Syouichi Katayama 2, Takako Kaneko-Kawano 2, Tetsuya Inazu 2, Yukihiko Kubota <sup>3</sup> and Masahiro Ito 1,3,\***


Received: 30 September 2019; Accepted: 5 November 2019; Published: 8 November 2019

**Abstract:** Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (*MECP2*), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (*CDKL5*) or forkhead box protein G1 (*FOXG1*) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order–disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT.

**Keywords:** 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
