Bioinformatic Analysis of Gene Variants from Gastroschisis Recurrence Identifies Multiple Novel Pathogenetic Pathways: Implication for the Closure of the Ventral Body Wall
Abstract
:1. Introduction
2. Results
2.1. Gene Functional Enrichment Analysis
2.2. Protein-Protein Interactions Network Analysis
2.3. Classification by Inheritance Pattern
2.4. Pathogenetic Pathways from Selected Genes Co-Segregating with Gastroschisis
3. Discussion
3.1. Novel Candidate Genes and Pathogenetic Pathways
3.2. Theories on the Failure of Body Wall Closure in Human and its Implication for Gastroschisis
3.3. Gastroschisis Clinical Susceptibility
4. Materials and Methods
4.1. Study Participants and Identification of Gene Variants from WES
4.2. Gene Functional Enrichment Analysis
4.3. Gene and Protein Network Analysis
4.4. Classification of Gene Variants by Inheritance Pattern
4.5. Pathogenetic Pathways from GO Functional Categories
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ADCY9 | Adenylate cyclase 9 gene |
ALPP | Alkaline phosphatase placental gene |
AOX1 | Aldehyde oxidase gene |
BCAS3 | Microtubule associated cell migration factor gene |
BP | Biological process |
CC | Cellular component |
CDYL | Chromodomain Y like gene |
CEACAM5 | Carcinoembryonic antigen related cell adhesion molecule gene |
CFAP65 | Cilia and flagella associated protein 65 gene |
COL6A3 | Collagen type VI alpha 3 chain gene |
CROCC | Ciliary rootlet coiled-coil, rootletin gene |
DPYD | Dihydropyrimidine dehydrogenase gene |
EVPL | Envoplakin gene |
F5 | Coagulation factor V gene |
FDR | False discovery rate |
FGFR4 | Fibroblast growth factor receptor 4 gene |
FGFRL1 | Fibroblast growth factor receptor like 1 gene |
GO | Gene ontology |
HHIP | Hedgehog interacting protein gene |
HIST1H2BB | Histone cluster 1 H2B family member B gene |
IFT140 | Intraflagellar transport 140 gene |
ITGA2 | Integrin subunit alpha 2 gene |
ITIH3 | Inter-alpha-trypsin inhibitor heavy chain 3 gene |
KDM5A | Lysine demethylase 5A gene |
KP | Kegg pathway |
KLK14 | Kallikrein related peptidase 14 gene |
MAP2K3 | Mitogen-activated protein kinase kinase 3 gene |
MF | Molecular function |
MYBPC2 | Myosin binding protein C, fast type gene |
NOTCH1 | Notch 1 gene |
OBSCN | Obscurin gene |
OR2C1 | Olfactory receptor family 2 subfamily C member 1 gene |
OR4C3 | Olfactory receptor family 4 subfamily C member 3 gene |
OR10G4 | Olfactory receptor family 10 subfamily G member 4 gene |
OR13F1 | Olfactory receptor family 13 subfamily F member 1 gene |
PDE4DIP | Phosphodiesterase 4D interacting protein gene |
PER2 | Period circadian regulator 2 gene |
PKD1 | Polycystin 1 gene |
PLEKHG4B | Pleckstrin homology and RhoGEF domain containing G4B gene |
PLOD1 | Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 gene |
PTPRD | Protein tyrosine phosphatase receptor type D gene |
RASGRP1 | RAS Guanyl releasing protein 1 gene |
RAPGEF1 | Rap guanine nucleotide exchange factor 1 gene |
RPS3 | Ribosomal protein S3 gene |
SGCD | Sarcoglycan delta gene |
SLC9A3 | Solute carrier family 9 member A3 gene |
SPATA17 | Spermatogenesis associated 17 gene |
SVS | SNP and variation suite |
THBS1 | Thrombospondin 1 gene |
TLR8 | Toll like receptor 8 gene |
UBE2NL | Ubiquitin conjugating enzyme E2 N like gene |
UGT1A3 | UDP Glucuronosyltransferase family 1 member A3 gene |
UGT1A4 | UDP Glucuronosyltransferase family 1 member A4 gene |
UGT1A5 | UDP Glucuronosyltransferase family 1 member A5 gene |
UGT1A6 | UDP Glucuronosyltransferase family 1 member A6 gene |
UGT1A7 | UDP Glucuronosyltransferase family 1 member A7 gene |
UGT1A8 | UDP Glucuronosyltransferase family 1 member A8 gene |
UGT1A9 | UDP Glucuronosyltransferase family 1 member A9 gene |
UGT1A10 | UDP Glucuronosyltransferase family 1 member A10 gene |
WD | Week of development |
WES | Whole exome sequence |
ZFHX3 | Zinc finger homeobox 3 gene |
ZNF717 | Zinc finger protein 717 gene |
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Category | GO term | Count | P Values (FDR) |
---|---|---|---|
BP | Xenobiotic glucuronidation | 8 | 7.99 × 10−11 |
BP | Negative regulation of glucuronosyltransferase activity | 7 | 1.42 × 10−9 |
BP | Flavonoid glucuronidation | 8 | 2.26 × 10−7 |
BP | Response to hormone | 30 | 1.65 × 10−4 |
BP | Response to chemical | 75 | 3.9 × 10−4 |
BP | Regulation of fatty acid metabolic process | 9 | 7.61 × 10−4 |
BP | Retinoic acid metabolic process | 4 | 2.05 × 10−2 |
CC | Integral component of membrane | 70 | 4.95 × 10−3 |
CC | Membrane part | 75 | 5.55 × 10−3 |
CC | Endoplasmic reticulum part | 23 | 8.92 × 10−3 |
CC | Cytoplasmic part | 102 | 2.18 × 10−2 |
MF | Glucuronosyltransferase activity | 8 | 1.58 × 10−6 |
MF | Retinoid binding | 5 | 7.67 × 10−3 |
MF | Active transmembrane transporter activity | 12 | 1.27 × 10−2 |
KP | Drug metabolism – other enzymes | 9 | 1.32 × 10−8 |
KP | Pentose and glucuronate interconversions | 8 | 2.83 × 10−8 |
KP | Retinol metabolism | 9 | 1.1 × 10−7 |
KP | Steroid hormone biosynthesis | 8 | 5.85 × 10−7 |
KP | Metabolism of xenobiotics by cytochrome P450 | 8 | 3.45 × 10−6 |
Pathogenetic Pathway | GO Terms | Genes Involved |
---|---|---|
Xenobiotic | Xenobiotic and flavonoid glucuronidation, retinol metabolism, negative regulation of fatty acid metabolic process, drug metabolic process, steroid hormone biosynthesis, negative regulation of cellular carbohydrate metabolic process, cellular response to xenobiotic stimulus, chemical carcinogenesis, negative regulation of lipid metabolic process, cellular hormone metabolic process | UGT1A4, UGT1A3, UGT1A10, UGT1A8, UGT1A7, UGT1A6, UGT1A5, AOX1, UGT1A9 |
Regulation of metabolic processes | Negative regulation of catalytic activity, negative regulation of molecular function, regulation of transferase activity, carboxylic acid metabolic process, response to growth factor, regulation of hydrolase activity, response to endogenous stimulus, detection of stimulus, regulation of protein modification process, folate biosynthesis | UGT1A4, UGT1A3, PLEKHG4B, COL6A3, RASGRP1, HHIP, THBS1, ADCY9, PER2, KDM5A, SLC9A3, BCAS3, OR2C1, OR4C3, RPS3, OR13F1, OBSCN, UGT1A10, UGT1A8, UGT1A7, UGT1A6, PKD1, UGT1A9, RAPGEF1, FGFRL1, ZFHX3, MAP2K3, FGFR4, ITGA2, TLR8, OR10G4, ITIH3, NOTCH1, ALPP, PLOD1 |
Regulation of cell adhesion | Cell-substrate adhesion, cell adhesion, regulation of cell junction assembly, negative regulation of anoikis, epidermis morphogenesis and development, epithelium development, cell-cell adhesion via plasma-membrane adhesion molecules, focal adhesion, wound healing | COL6A3, RASGRP1, THBS1, CEACAM5, PTPRD, BCAS3, HHIP, PKD1, RAPGEF1, FGFRL1, ITGA2, F5, KLK14, EVPL, FGFR4, PLOD1, NOTCH1, MYBPC2 |
Regulation of gene expression | Circadian regulation of gene expression, developmental biology, multi-organism reproductive process, negative regulation of nucleic acid-templated transcription | PER2, ZNF717, KDM5A, ZFHX3, COL6A3, RASGRP1, KLK14, HIST1H2BB, CDYL, EVPL, FGFR4, ITGA2, NOTCH1 |
Inflammatory response | Toll receptor signaling pathway, inflammatory response, regulation of cytokine biosynthetic process | UBE2NL, MAP2K3, TLR8, RASGRP1, THBS1, AOX1, ITGA2, NOTCH1 |
Regulation of vascular development | Circulatory system development, blood vessel development, hemostasis, blood coagulation | HHIP, RASGRP1, THBS1, CEACAM5, ITGA2, F5, ITIH3, BCAS3, SGCD, PKD1, RAPGEF1, FGFRL1, NOTCH1 |
Keratinization | Formation of the cornified envelope | KLK14, EVPL |
Left-right symmetry | Left-right axis specification | NOTCH1 |
Epigenetic | Histone modification, chromatin organization, DNA methylation | PER2, KDM5A, HIST1H2BB, CDYL |
Ubiquitination | Protein ubiquitination | UBE2NL, PER2, RPS3 |
Regulation of protein synthesis | Protein-containing complex assembly | RASGRP1, RPS3, PDE4DIP, FGFRL1, HIST1H2BB, F5 |
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Salinas-Torres, V.M.; Gallardo-Blanco, H.L.; Salinas-Torres, R.A.; Cerda-Flores, R.M.; Lugo-Trampe, J.J.; Villarreal-Martínez, D.Z.; Martínez de Villarreal, L.E. Bioinformatic Analysis of Gene Variants from Gastroschisis Recurrence Identifies Multiple Novel Pathogenetic Pathways: Implication for the Closure of the Ventral Body Wall. Int. J. Mol. Sci. 2019, 20, 2295. https://doi.org/10.3390/ijms20092295
Salinas-Torres VM, Gallardo-Blanco HL, Salinas-Torres RA, Cerda-Flores RM, Lugo-Trampe JJ, Villarreal-Martínez DZ, Martínez de Villarreal LE. Bioinformatic Analysis of Gene Variants from Gastroschisis Recurrence Identifies Multiple Novel Pathogenetic Pathways: Implication for the Closure of the Ventral Body Wall. International Journal of Molecular Sciences. 2019; 20(9):2295. https://doi.org/10.3390/ijms20092295
Chicago/Turabian StyleSalinas-Torres, Víctor M., Hugo L. Gallardo-Blanco, Rafael A. Salinas-Torres, Ricardo M. Cerda-Flores, José J. Lugo-Trampe, Daniel Z. Villarreal-Martínez, and Laura E. Martínez de Villarreal. 2019. "Bioinformatic Analysis of Gene Variants from Gastroschisis Recurrence Identifies Multiple Novel Pathogenetic Pathways: Implication for the Closure of the Ventral Body Wall" International Journal of Molecular Sciences 20, no. 9: 2295. https://doi.org/10.3390/ijms20092295