title: Genomic and in silico analyses of CRBN gene and thalidomide embryopathy in humans.
abstract: Thalidomide causes Thalidomide Embryopathy (TE), but is largely used to treat several conditions. Investigations with Cereblon, a thalidomide target protein encoded by CRBN gene, have helped to understand thalidomide therapeutic and teratogenic properties. We sequenced CRBN-thalidomide binding region in 38 TE individuals and 136 Brazilians without congenital anomalies, and performed in silico analyses. Eight variants were identified, seven intronic and one in 3'UTR. TE individuals had rare variants in higher frequency than the non-affected group (p=0.04). The genotype rs1620675 CC was related to neurological anomalies in TE individuals (p=0.004). Bioinformatics analysis suggested this genotype leads to potential alterations in splicing sites and binding to transcription factors. Comparison of the Cereblon-thalidomide binding domains in mammals demonstrated that CRBN is highly conserved across species. All the variants require evaluation in functional assays in order to understand their role in Cereblon-thalidomide binding and complex interactions that lead to TE.
authors.affiliation: INAGEMP-Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil; Teratogen Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil; Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Brazil. Electronic address: fslvianna@gmail.com.
authors.forename: Fernanda Sales Luiz
authors.initials: FS
authors.lastname: Vianna
authors.affiliation: INAGEMP-Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil; Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Thayne Woycinck
authors.initials: TW
authors.lastname: Kowalski
authors.affiliation: Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Post-graduate program in Epidemiology, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Tovo-Rodrigues
authors.affiliation: Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Alice
authors.initials: A
authors.lastname: Tagliani-Ribeiro
authors.affiliation: Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Bibiane Armiliato
authors.initials: BA
authors.lastname: Godoy
authors.affiliation: INAGEMP-Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil; Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Lucas Rosa
authors.initials: LR
authors.lastname: Fraga
authors.affiliation: INAGEMP-Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil; Teratogen Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil; Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; School of Medicine, Pontificial Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Maria Teresa Vieira
authors.initials: MT
authors.lastname: Sanseverino
authors.affiliation: Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Mara Helena
authors.initials: MH
authors.lastname: Hutz
authors.affiliation: INAGEMP-Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil; Teratogen Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil; Post-Graduate program in Genetics and Molecular Biology, Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Lavínia
authors.initials: L
authors.lastname: Schuler-Faccini
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000235:genetics*; D000015:Abnormalities, Multiple / Q000139:chemically induced / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D001938:Brazil; D003198:Computer Simulation; D005315:Fetal Diseases / Q000139:chemically induced / Q000235:genetics*; D023281:Genomics; D006801:Humans; D010447:Peptide Hydrolases / Q000235:genetics*; D013723:Teratogens / Q000633:toxicity*; D013792:Thalidomide / Q000633:toxicity*; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D013723:Teratogens; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases
keywords: CRBN; Cereblon; Teratogenesis; Thalidomide; Thalidomide embryopathy