Role of Overexpressed Transcription Factor FOXO1 in Fatal Cardiovascular Septal Defects in Patau Syndrome: Molecular and Therapeutic Strategies

Abstract

Patau Syndrome (PS), characterized as a lethal disease, allows less than 15% survival over the first year of life. Most deaths owe to brain and heart disorders, more so due to septal defects because of altered gene regulations. We ascertained the cytogenetic basis of PS first, followed by molecular analysis and docking studies. Thirty-seven PS cases were referred from the Department of Pediatrics, King Abdulaziz University Hospital to the Center of Excellence in Genomic Medicine Research, Jeddah during 2008 to 2018. Cytogenetic analyses were performed by standard G-band method and trisomy13 were found in all the PS cases. Studies have suggested that genes of chromosome 13 and other chromosomes are associated with PS. We, therefore, did molecular pathway analysis, gene interaction, and ontology studies to identify their associations. Genomic analysis revealed important chr13 genes such as FOXO1, Col4A1, HMGBB1, FLT1, EFNB2, EDNRB, GAS6, TNFSF1, STARD13, TRPC4, TUBA3C, and TUBA3D, and their regulatory partners on other chromosomes associated with cardiovascular disorders, atrial and ventricular septal defects. There is strong indication of involving FOXO1 (Forkhead Box O1) gene-a strong transcription factor present on chr13, interacting with many septal defects link genes. The study was extended using molecular docking to find a potential drug lead for overexpressed FOXO1 inhibition. The phenothiazine and trifluoperazine showed efficiency to inhibit overexpressed FOXO1 protein, and could be potential drugs for PS/trisomy13 after validation.

Keywords: FOXO1; Patau Syndrome; and drug design; bioinformatics; cytogenetics; molecular docking; molecular pathways; transcription factor.

Figure 1

Karyotyping result; (A) Normal Karyotype of Healthy female and (B) Trisomy 13 in all cases (male = 20 and female = 17) of Patau Syndrome. Red arrow shows trisomy 13.

Figure 2

Estrogen-mediated S-phase Entry pathway derived from 308 protein coding genes of triosomy 13 (chromosome 13) using Ingenuity Pathway Analysis Tool.

Figure 3

Protein–protein Interaction Partners (GATA4, NKX2-5, SIRT1, CITED, NFATc1, TBX5) of FOXO1.

Figure 4

Molecular docking of phenothiazine with FOXO1 protein. (A) Depicting the molecular structure of phenothiazine; (B) Structure visualization of FOXO1 protein bound with ligand PTZ. The interacting residues are labeled in the binding site. (C) 2D plot of phenothiazine of FOXO1 showing ligand–protein interaction profiled by AutoDock software of Docking Server. Leu163, Leu168, Lys171, Trp189, Val194, Pro195, and Ser193 residues of FOXO1 showed crucial interactions with the phenothiazine.

Figure 5

Molecular docking of trifluoperazine with FOXO1 protein. (A) Depicting the molecular structure of trifluoperazine; (B) Structure visualization of FOXO1 protein bound with ligand TFP. The binding site is shown and the interacting residues are labeled. (C) 2D plot of trifluoperazine of FOXO1 showing ligand–protein interaction profiled by AutoDock software of Docking Server. Leu183, Tyr187, Leu217, Arg225, Arg234, Ser184, Ser218, Ser234, Ser235 and Trp237 residues of FOXO1 showed crucial interactions with the trifluoperazine.