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

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.

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

“…In a previous study from our group, we performed an analysis of SALL4 in TE individuals and identified 15 variants. Of these 15, ten were located in exons, seven synonymous and three missense 24 . The lack of exonic variants identified in our study prevented the analysis of the effects of combined SALL4 and CRBN variants.…”

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy

“…Historical reports estimated that 20–50% of the human embryos exposed to thalidomide actually developed TE ( Newman, 1986 ). Our studies have reported variants in the TE individuals when compared to Brazilians without congenital anomalies ( Vianna et al, 2016 ; Gomes et al, 2019 ; Kowalski et al, 2020 ). The rare variants we identified in the canonical sequences of insensitive species were absent in that TE sample.…”

“…Notwithstanding, TE in humans is considered heterogeneous, because the phenotypic presentation is variable, an effect that is not explained only by SALL4 or CRBN variants ( Gomes et al, 2019 ; Kowalski et al, 2020 ). Considering TE intra- and interspecific variability, the aim of this research was to perform a comparative analysis in the main proteins already associated with thalidomide mechanisms of action, across different species, affected or not by classic TE.…”

Genetic evaluation of HAND2 gene and its effects on thalidomide embryopathy

“…This variation is described to occur due to mother–child genetic susceptibility (Cassina et al, 2012; Vargesson & Fraga, 2017). Many genes have already been studied in relation to their role on genetic susceptibility to TE, including those related to embryo development, angiogenesis and CRBN , which encodes Cereblon protein, a direct target of Thalidomide (Gomes et al, 2018; Gomes et al, 2019; Gomes et al, 2021; Kowalski et al, 2016; Kowalski et al, 2020; Vianna et al, 2016). It has been shown that variants on NOS3 gene were associated to TE and provide genetic susceptibility to TE.…”

“…Previous studies from our group have investigated TBX5 gene in TE individuals looking for genetic variants potentially involved to the susceptibility to this condition (Gomes et al, 2019). Taking into account the TBX5‐HAND2 interaction and thalidomide and that altered HAND2 function was already associated to heart and limbs malformations, a molecular investigation on HAND2 could bring novelty on how this gene influences limbs and heart defects observed in TE individuals.…”