Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684595 | PMC |
| http://dx.doi.org/10.1038/s41598-019-47739-8 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Human Genetics of Ventricular Septal Defect.
Adv Exp Med Biol
June 2024
Cardiovascular Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Article Synopsis
- Ventricular septal defects (VSDs) are common congenital heart diseases, making up about 40% of cardiac malformations and can occur alone or with other defects.
- The genetic causes of VSD are complex, involving chromosomal abnormalities and gene mutations, including known syndromes like DiGeorge and Holt-Oram.
- Recent advancements like comparative genomic hybridization have revealed numerous copy number variations linked to VSD, highlighting the genetic diversity in affected patients.
Sall genes regulate hindlimb initiation in mouse embryos.
Genetics
May 2024
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Vertebrate limbs start to develop as paired protrusions from the lateral plate mesoderm at specific locations of the body with forelimb buds developing anteriorly and hindlimb buds posteriorly. During the initiation process, limb progenitor cells maintain active proliferation to form protrusions and start to express Fgf10, which triggers molecular processes for outgrowth and patterning. Although both processes occur in both types of limbs, forelimbs (Tbx5), and hindlimbs (Isl1) utilize distinct transcriptional systems to trigger their development.
View Article and Find Full Text PDFIntegrative Role of the SALL4 Gene: From Thalidomide Embryopathy to Genetic Defects of the Upper Limb, Internal Organs, Cerebral Midline, and Pituitary.
Horm Res Paediatr
April 2024
Department of Paediatrics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czechia,
Background: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s.
Summary: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis.
Identification of SALL4 Expressing Islet-1+ Cardiovascular Progenitor Cell Clones.
Int J Mol Sci
January 2023
Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
The utilization of cardiac progenitor cells (CPCs) has been shown to induce favorable regenerative effects. While there are various populations of endogenous CPCs in the heart, there is no consensus regarding which population is ideal for cell-based regenerative therapy. Early-stage progenitor cells can be differentiated into all cardiovascular lineages, including cardiomyocytes and endothelial cells.
View Article and Find Full Text PDFComparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy.
Front Genet
June 2021
Post-Graduation Program in Genetics and Molecular Biology, PPGBM, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil.
The identification of thalidomide-Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!