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. 2023 May 21;12(10):1437.
doi: 10.3390/cells12101437.

Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders

Eric Frankel  1 , Avijit Podder  2 , Megan Sharifi  1 , Roshan Pillai  1 , Newell Belnap  1   3 , Keri Ramsey  3 , Julius Dodson  1 , Pooja Venugopal  1 , Molly Brzezinski  1 , Lorida Llaci  1   2 , Brittany Gerald  1 , Gabrielle Mills  1 , Meredith Sanchez-Castillo  3 , Chris D Balak  1 , Szabolcs Szelinger  1 , Wayne M Jepsen  1 , Ashley L Siniard  1 , Ryan Richholt  1 , Marcus Naymik  1 , Isabelle Schrauwen  4 , David W Craig  5 , Ignazio S Piras  1 , Matthew J Huentelman  1   2 , Nicholas J Schork  2   6 , Vinodh Narayanan  1   3 , Sampathkumar Rangasamy  1   3
Affiliations

Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders

Eric Frankel et al. Cells. .

Abstract

Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to have an overlapping neurological phenotype with RTT but are lacking a mutation in a gene that causes classical or atypical RTT can be described as having a 'Rett-syndrome-like phenotype (RTT-L). Here, we report eight patients from our cohort diagnosed as having RTT-L who carry mutations in genes unrelated to RTT. We annotated the list of genes associated with RTT-L from our patient cohort, considered them in the light of peer-reviewed articles on the genetics of RTT-L, and constructed an integrated protein-protein interaction network (PPIN) consisting of 2871 interactions connecting 2192 neighboring proteins among RTT- and RTT-L-associated genes. Functional enrichment analysis of RTT and RTT-L genes identified a number of intuitive biological processes. We also identified transcription factors (TFs) whose binding sites are common across the set of RTT and RTT-L genes and appear as important regulatory motifs for them. Investigation of the most significant over-represented pathway analysis suggests that HDAC1 and CHD4 likely play a central role in the interactome between RTT and RTT-L genes.

Keywords: Rett syndrome; Rett-syndrome-like phenotype; atypical RTT syndrome; methyl-CpG-binding protein 2; neurodevelopmental disorders; overlapping phenotype; protein–protein interaction network.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
RTT and RTT-L genes connecting PPIN: (A) The experimental protein–protein interactions (PPIs) (in general—non-tissue-specific) of 4 RTT and 58 RTT-L genes together identified 2192 interacting partners in human interactome. The topological assessments show the degree (connectivity) and betweenness centrality distribution (box plot) of the genes and highlighted the hub-like RTT, RTT-L, and interactor genes with higher degree of connectivity in the PPIN. Genes such as NTNG1 (RTT) and ST3GAL5 (RTT-L) are not closely connected with the main network but share distinct set of interactions with other proteins in human interactome. (B) A physical protein–protein interaction (PPI) graph of 4 RTT and 58 RTT-L genes together identified 201 and 1563 direct interacting partners, respectively, in the human-brain-specific network. The Venn diagram highlights the common interactors present in both RTT and RTT-L genes’ specific PPINs. RTT—Rett syndrome and RTT-L—Rett-like Syndrome.
Figure 1
Figure 1
RTT and RTT-L genes connecting PPIN: (A) The experimental protein–protein interactions (PPIs) (in general—non-tissue-specific) of 4 RTT and 58 RTT-L genes together identified 2192 interacting partners in human interactome. The topological assessments show the degree (connectivity) and betweenness centrality distribution (box plot) of the genes and highlighted the hub-like RTT, RTT-L, and interactor genes with higher degree of connectivity in the PPIN. Genes such as NTNG1 (RTT) and ST3GAL5 (RTT-L) are not closely connected with the main network but share distinct set of interactions with other proteins in human interactome. (B) A physical protein–protein interaction (PPI) graph of 4 RTT and 58 RTT-L genes together identified 201 and 1563 direct interacting partners, respectively, in the human-brain-specific network. The Venn diagram highlights the common interactors present in both RTT and RTT-L genes’ specific PPINs. RTT—Rett syndrome and RTT-L—Rett-like Syndrome.
Figure 2
Figure 2
Functional Enrichment Analysis for RTT and RTT-L Genes: (A) A gene-set-based enrichment analysis results for RTT (N1 = 4) and RTT-L (N2 = 58) genes together using the Gene Ontology (biological process), pathway databases (KEGG, REACTOME, and WIKIPATHWAYS) and regulatory motifs databases (transcription factors and microRNA). The X-axis represents the number of overlapping genes from our given gene sets in each enrichment term. The dot size highlights the enrichment statistics (p-values) for each term, and the dot color represents the source of each term in the respective databases. (B) The RTT and RTT-L genes are highlighted in one of the well-documented WikiPathways (WP4312) for Rett-syndrome-causing genes—Homo sapiens. We identified a total of 5 genes (highlighted in cyan color) that are part of the PPIN, which share common interaction with both RTT and RTT-L genes (as shown in Figure 1A). Genes such as HDAC1 and CHD4 play a central role in the underline pathway.
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