Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Laboratório de Genética Médica e Evolução, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Sci Rep. 2019 Aug 6;9(1):11413. doi: 10.1038/s41598-019-47739-8.
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.
沙利度胺被广泛用于多种疾病；然而，它会导致怀孕期间暴露的胚胎畸形。目前尚未完全了解沙利度胺影响胚胎发育的机制。表型相似性使 TE 成为 ESCO2、SALL4 和 TBX5 基因突变引起的综合征的表型副本。最近，SALL4 和 TBX5 被证明是沙利度胺的靶标。为了了解这些基因是否在 TE 发育中起作用，我们在 27 名 TE 患者中对它们进行了测序；我们通过 GSE63935 的差异基因表达 (DGE) 分析验证了沙利度胺如何在人多能干细胞 (hPSC) 中影响它们；我们通过互作网络分析评估了这些基因如何在功能上相关。我们在 ESCO2 中鉴定出 8 个变体，在 SALL4 中鉴定出 15 个变体，在 TBX5 中鉴定出 15 个变体。我们将等位基因频率与 ExAC、1000 Genomes 和 ABraOM 数据库的数据进行了比较；其中 8 个变体存在显著差异（p < 0.05）。SALL4 和 TBX5 中的 11 个变体先前与心脏疾病或畸形有关；然而，在 TE 样本中没有关联。变体效应预测工具显示 97%的变体有可能影响这些基因的调控。DGE 分析显示，暴露于沙利度胺后 hPSC 中的 ESCO2 显著减少。
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