Journal Article

The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis

Fraga, Lucas Rosa, Sanseverino, Maria Teresa Vieira, Macedo, Gabriel S., Schuler-Faccini, Lavínia, Kowalski, Thayne Woycinck, Vianna, Fernanda Sales Luiz, Gomes, Julia do Amaral

2019

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 631/208 / 631/337 / Abnormalities, Multiple - chemically induced / Abnormalities, Multiple - genetics / Acetyltransferases - genetics / Brazil / Cell Line / Chromosomal Proteins, Non-Histone - genetics / Coronary artery disease / Craniofacial Abnormalities - chemically induced / Craniofacial Abnormalities - genetics / Datasets as Topic / Duane Retraction Syndrome - chemically induced / Duane Retraction Syndrome - genetics / Ectromelia - chemically induced / Ectromelia - genetics / Embryos / Female / Gene expression / Gene Expression Profiling / Gene Frequency / Gene regulation / Genetic Predisposition to Disease / Genomes / Heart Defects, Congenital - chemically induced / Heart Defects, Congenital - genetics / Heart diseases / Heart Septal Defects, Atrial - chemically induced / Heart Septal Defects, Atrial - genetics / Humanities and Social Sciences / Humans / Hypertelorism - chemically induced / Hypertelorism - genetics / Leprosy - drug therapy / Lower Extremity Deformities, Congenital - chemically induced / Lower Extremity Deformities, Congenital - genetics / Male / multidisciplinary / Mutation / Pluripotency / Pluripotent Stem Cells / Polymorphism, Single Nucleotide / Pregnancy / Pregnancy Complications - drug therapy / Protein Interaction Maps - genetics / Science / Science (multidisciplinary) / Stem cells / T-Box Domain Proteins - genetics / Teratogenesis / Teratogenesis - drug effects / Teratogenesis - genetics / Thalidomide / Thalidomide - adverse effects / Transcription Factors - genetics / Upper Extremity Deformities, Congenital - chemically induced / Upper Extremity Deformities, Congenital - genetics