Genetic susceptibility to thalidomide embryopathy in humans: Study of candidate development genes

Gomes, João Luiz Ellera; Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Tovo‐Rodrigues, Luciana; Sanseverino, Maria Teresa Vieira; Schüler‐Faccini, Lavínia; Vianna, Fernanda Sales Luiz

doi:10.1002/bdr2.1163

Cited by 4 publications

(2 citation statements)

References 27 publications

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“…The rare variants we identified in the canonical sequences of insensitive species were absent in that TE sample. The polymorphism rs1042522 of TP53 was genotyped in TE and unaffected individuals; however, its frequency was similar in both groups ( Gomes et al, 2017 ). Despite that, rs1042522 is a functionally well-characterized polymorphism ( Dumont et al, 2003 ) that could also help to explain interspecific variability to thalidomide-teratogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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. Here, we performed a comparative analysis of proteins experimentally established as affected by thalidomide exposure, evaluating 14 species. The comparative analysis, regarding synteny, neighborhood, and protein conservation, was performed in 42 selected genes. Differential co-expression analysis was performed, using a publicly available assay, GSE61306, which evaluated mouse embryonic stem cells (mESC) exposed to thalidomide. The comparative analyses evidenced 20 genes in the upstream neighborhood of NOS3, which are different between the species who develop, or not, the classic TE phenotype. Considering protein sequence alignments, RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had the biggest number of variants reported in unaffected species. In co-expression analysis, Crbn was a gene identified as a driver of the co-expression of other genes implicated in genetic, non-teratogenic, limb reduction defects (LRD), such as Tbx5, Esco2, Recql4, and Sall4; Crbn and Sall4 were shown to have a moderate co-expression correlation, which is affected after thalidomide exposure. Hence, even though the classic TE phenotype is not identified in mice, a deregulatory Crbn-induced mechanism is suggested in this animal. Functional studies are necessary, especially evaluating the genes responsible for LRD syndromes and their interaction with thalidomide–Cereblon.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Genetic evaluation of HAND2 gene and its effects on thalidomide embryopathy

Rengel

Kowalski

Bremm

et al. 2022

Birth Defects Research

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Background HAND2 is a transcription factor important for embryonic development, required for limbs and cardiovascular development. Thalidomide is a drug responsible to a spectrum of congenital anomalies known as Thalidomide Embryopathy (TE), which includes mainly limb and heart defects. It is known that HAND2 interaction with TBX5, an important protein for limbs and heart development, is inhibited by Thalidomide. The aim of this study was to evaluate and characterize HAND2 in the context of TE, and to evaluate its variability in TE individuals. Methods DNA from 35 TE subjects was extracted from saliva samples and PCR was performed for amplification and Sanger sequencing of HAND2 coding sequence. Results The analysis showed only one variant; a synonymous variant p.P51 (rs59621536) in exon 1 found in three individuals. Further in silico evaluation confirmed highly HAND2 conservation, being the 3′UTR the most polymorphic region of the gene. Additional computational analyses classified the variant as neutral, without alteration in splicing and miRNA sites. In silico predictions pointed to alteration of two CpG islands adjacent to the variant; however, we did not observe any alterations on the methylation pattern of HAND2 gene in our sample. Moreover, alteration of the binding site of MeCP2, a nuclear protein involved in DNA methylation, was predicted along with alteration in HAND2 mRNA structure. Conclusions Considering HAND2 being a well conserved gene, further studies with a larger sample should be performed to evaluate the role this gene on genetic susceptibility to TE.

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