CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation.,Scientific Reports

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CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation.
Scientific Reports ( IF 3.8 ) Pub Date : 2020-01-21 , DOI: 10.1038/s41598-020-57512-x
Thayne Woycinck Kowalski _{1,

2,

3,

4,

5,

6} , Julia do Amaral Gomes _{1,

2,

3,

4,

5} , Gabriela Barreto Caldas Garcia ₁ , Lucas Rosa Fraga _{2,

3,

4,

5,

7} , Vanessa Rodrigues Paixao-Cortes ₈ , Mariana Recamonde-Mendoza _{9,

10} , Maria Teresa Vieira Sanseverino _{1,

2,

3,

5,

11} , Lavinia Schuler-Faccini _{1,

2,

3,

5} , Fernanda Sales Luiz Vianna _{1,

2,

3,

4,

5,

12}

Affiliation

Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Laboratory of Medical and Population Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
National Institute of Population Medical Genetics (INAGEMP), Porto Alegre, Brazil.
Genomic Medicine Laboratory, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.
National System of Information on Teratogenic Agents (SIAT), Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.
Complexo de Ensino Superior de Cachoeirinha (CESUCA), Cachoeirinha, Brazil.
Department of Morphological Sciences, Institute of Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Institute of Biology, Universidade Federal da Bahia (UFBA), Salvador, Brazil.
Institute of Informatics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Bioinformatics Core, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.
School of Medicine - Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil.
Immunobiology and Immunogenetics Laboratory, Departamento de Genética, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

The Cereblon-CRL4 complex has been studied predominantly with regards to thalidomide treatment of multiple myeloma. Nevertheless, the role of Cereblon-CRL4 in Thalidomide Embryopathy (TE) is still not understood. Not all embryos exposed to thalidomide develop TE, hence here we evaluate the role of the CRL4-Cereblon complex in TE variability and susceptibility. We sequenced CRBN, DDB1, CUL4A, IKZF1, and IKZF3 in individuals with TE. To better interpret the variants, we suggested a score and a heatmap comprising their regulatory effect. Differential gene expression after thalidomide exposure and conservation of the CRL4-Cereblon protein complex were accessed from public repositories. Results suggest a summation effect of Cereblon variants on pre-axial longitudinal limb anomalies, and heatmap scores identify the CUL4A variant rs138961957 as potentially having an effect on TE susceptibility. CRL4-Cereblon gene expression after thalidomide exposure and CLR4-Cereblon protein conservation does not explain the difference in Thalidomide sensitivity between species. In conclusion, we suggest that CRL4-Cereblon variants act through several regulatory mechanisms, which may influence CRL4-Cereblon complex assembly and its ability to bind thalidomide. Human genetic variability must be addressed not only to further understand the susceptibility to TE, but as a crucial element in therapeutics, including in the development of pharmacogenomics strategies.

中文翻译：

沙利度胺胚胎病中的 CRL4-Cereblon 复合体：一项转化研究。

Cereblon-CRL4 复合物主要针对多发性骨髓瘤的沙利度胺治疗进行了研究。尽管如此，Cereblon-CRL4 在沙利度胺胚胎病 (TE) 中的作用仍不清楚。并非所有暴露于沙利度胺的胚胎都会发生 TE，因此我们在此评估 CRL4-Cereblon 复合物在 TE 变异性和易感性中的作用。我们对 TE 患者的 CRBN、DDB1、CUL4A、IKZF1 和 IKZF3 进行了测序。为了更好地解释变体，我们建议了一个分数和一个包含它们的调节作用的热图。从公共存储库访问沙利度胺暴露后的差异基因表达和 CRL4-Cereblon 蛋白复合物的保护。结果表明，Cereblon 变异对轴向前纵向肢体异常的总和效应，和热图分数确定 CUL4A 变体 rs138961957 可能对 TE 易感性产生影响。沙利度胺暴露后的 CRL4-Cereblon 基因表达和 CLR4-Cereblon 蛋白保护不能解释物种间沙利度胺敏感性的差异。总之，我们建议 CRL4-Cereblon 变体通过几种调节机制起作用，这可能会影响 CRL4-Cereblon 复合物组装及其结合沙利度胺的能力。必须解决人类遗传变异性问题，不仅要进一步了解对 TE 的易感性，还要将其作为治疗的关键要素，包括药物基因组学策略的开发。沙利度胺暴露后的 CRL4-Cereblon 基因表达和 CLR4-Cereblon 蛋白保护不能解释物种间沙利度胺敏感性的差异。总之，我们建议 CRL4-Cereblon 变体通过几种调节机制起作用，这可能会影响 CRL4-Cereblon 复合物组装及其结合沙利度胺的能力。必须解决人类遗传变异性问题，不仅要进一步了解对 TE 的易感性，还要将其作为治疗的关键要素，包括药物基因组学策略的开发。沙利度胺暴露后的 CRL4-Cereblon 基因表达和 CLR4-Cereblon 蛋白保护不能解释物种间沙利度胺敏感性的差异。总之，我们建议 CRL4-Cereblon 变体通过几种调节机制起作用，这可能会影响 CRL4-Cereblon 复合物组装及其结合沙利度胺的能力。必须解决人类遗传变异性问题，不仅要进一步了解对 TE 的易感性，还要将其作为治疗的关键要素，包括药物基因组学策略的开发。

更新日期：2020-01-22

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