Journal Article

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

Recamonde-Mendoza, Mariana, Garcia, Gabriela Barreto Caldas, Fraga, Lucas Rosa, Sanseverino, Maria Teresa Vieira, Kowalski, Thayne Woycinck, Vianna, Fernanda Sales Luiz, Paixao-Cortes, Vanessa Rodrigues, Gomes, Julia do Amaral, Schuler-Faccini, Lavinia

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38 / 38/23 / 38/39 / 38/77 / 45 / 631/208/514/2254 / 631/337 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Adolescent / Adult / Child / Drug development / Embryo, Mammalian / Embryonic Development - genetics / Embryos / Female / Fetal Diseases - chemically induced / Fetal Diseases - genetics / Gene Expression / Genetic Predisposition to Disease - genetics / Genetic variability / Genetic Variation / Humanities and Social Sciences / Humans / Male / Middle Aged / multidisciplinary / Multiple myeloma / Pharmacogenomics / Protein Binding / Science / Science (multidisciplinary) / Thalidomide / Thalidomide - adverse effects / Thalidomide - metabolism / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Upper Extremity Deformities, Congenital - chemically induced / Upper Extremity Deformities, Congenital - genetics / Young Adult