CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

Abstract

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.

Genetic Susceptibility to Drug Teratogenicity: A Systematic Literature Review

“…In these studies, the CRBN and NOS3 , which are part of the CLR4-Cereblon complex, and act on angiogenic and oxidative stress processes, respectively, were reported to be associated with an increased risk of developing thalidomide embryopathy, a phenotypic spectrum of malformations characterized by limb reduction defects (Vargesson, 2009 ). The CRBN genetic variants rs1045433 and rs1620675 were associated with an increased risk of pre-axial limb anomalies and neurological anomalies, respectively (Vianna et al, 2016 ; Kowalski et al, 2020 ). In addition, NOS3 has deleterious variants (rs2070744, rs1799983, and rs61722009) associated with susceptibility to developing thalidomide embryopathy (Vianna et al, 2013 ; Kowalski et al, 2016 ).…”

“…Thalidomide is one of the oldest known teratogenic agents, causing thalidomide embryopathy (Vargesson, 2009 ). The reviewed studies on thalidomide focused on examining genes encoding proteins important in angiogenesis and oxidative stress, or proteins that are part of the CLR4-Cereblon complex, all of which are known to be associated with thalidomide teratogenicity (Therapontos et al, 2009 ; Ito et al, 2010 ; Vianna et al, 2013 , 2016 ; Ha et al, 2016 ; Kowalski et al, 2016 , 2017 , 2020 ).…”

“…Teratogenesis is a complex, multifactorial process and an understanding of both genetic and environmental factors is pivotal to predicting the effects of a teratogen (Kowalski et al, 2020 ). Furthermore, multiple genetic variants with small individual effects are likely to be associated with teratogenic susceptibility (Edwards et al, 2013 ).…”

Data_Sheet_1.docx

“…Thalidomide is one of the oldest known teratogenic agents, causing thalidomide embryopathy (Vargesson, 2009). The reviewed studies on thalidomide focused on examining genes encoding proteins important in angiogenesis and oxidative stress, or proteins that are part of the CLR4-Cereblon complex, all of which are known to be associated with thalidomide teratogenicity (Therapontos et al, 2009;Ito et al, 2010;Vianna et al, 2013Vianna et al, , 2016Ha et al, 2016;Kowalski et al, 2016Kowalski et al, , 2017Kowalski et al, , 2020.…”

“…In these studies, the CRBN and NOS3, which are part of the CLR4-Cereblon complex, and act on angiogenic and oxidative stress processes, respectively, were reported to be associated with an increased risk of developing thalidomide embryopathy, a phenotypic spectrum of malformations characterized by limb reduction defects (Vargesson, 2009). The CRBN genetic variants rs1045433 and rs1620675 were associated with an increased risk of pre-axial limb anomalies and neurological anomalies, respectively (Vianna et al, 2016;Kowalski et al, 2020). In addition, NOS3 has deleterious variants (rs2070744, rs1799983, and rs61722009) associated with susceptibility to developing thalidomide embryopathy (Vianna et al, 2013;Kowalski et al, 2016).…”