Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abnormalities, Multiple / chemically induced
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Abnormalities, Multiple / genetics
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Acetyltransferases / genetics*
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Brazil
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Cell Line
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Chromosomal Proteins, Non-Histone / genetics*
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Craniofacial Abnormalities / chemically induced
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Craniofacial Abnormalities / genetics
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Datasets as Topic
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Duane Retraction Syndrome / chemically induced
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Duane Retraction Syndrome / genetics
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Ectromelia / chemically induced
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Ectromelia / genetics
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Female
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Gene Expression Profiling
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Gene Frequency
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Genetic Predisposition to Disease*
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Heart Defects, Congenital / chemically induced
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Heart Defects, Congenital / genetics
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Heart Septal Defects, Atrial / chemically induced
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Heart Septal Defects, Atrial / genetics
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Humans
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Hypertelorism / chemically induced
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Hypertelorism / genetics
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Leprosy / drug therapy
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Lower Extremity Deformities, Congenital / chemically induced
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Lower Extremity Deformities, Congenital / genetics
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Male
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Mutation
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Pluripotent Stem Cells
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Polymorphism, Single Nucleotide
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Pregnancy
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Pregnancy Complications / drug therapy
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Protein Interaction Maps / genetics
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T-Box Domain Proteins / genetics*
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Teratogenesis / drug effects
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Teratogenesis / genetics*
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Thalidomide / adverse effects*
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Transcription Factors / genetics*
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Upper Extremity Deformities, Congenital / chemically induced
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Upper Extremity Deformities, Congenital / genetics
Substances
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Chromosomal Proteins, Non-Histone
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SALL4 protein, human
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T-Box Domain Proteins
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T-box transcription factor 5
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Transcription Factors
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Thalidomide
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Acetyltransferases
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ESCO2 protein, human
Supplementary concepts
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Holt-Oram syndrome
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Roberts Syndrome