Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90-95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we ini...
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todo:paper_20452322_v6_n_p_Bruque2023-10-03T16:38:12Z Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations Bruque, C.D. Delea, M. Fernández, C.S. Orza, J.V. Taboas, M. Buzzalino, N. Espeche, L.D. Solari, A. Luccerini, V. Alba, L. Nadra, A.D. Dain, L. CYP21A2 protein, human steroid 21 monooxygenase chemistry computer simulation congenital adrenal hyperplasia genetic variation genetics human metabolism molecular model mutation protein conformation protein stability single nucleotide polymorphism structure activity relation Adrenal Hyperplasia, Congenital Computer Simulation Genetic Variation Humans Models, Molecular Mutation Polymorphism, Single Nucleotide Protein Conformation Protein Stability Steroid 21-Hydroxylase Structure-Activity Relationship Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90-95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we initially classified all known mutants (n = 343) according to their putative functional impacts, which were either reported in the literature or inferred from structural models. We then performed a detailed analysis on the subset of mutations believed to exclusively impact protein stability. For those mutants, the predicted stability was calculated and correlated with the variant's expected activity. A high concordance was obtained when comparing our predictions with available in vitro residual activities and/or the patient's phenotype. The predicted stability and derived activity of all reported mutations and SNPs lacking functional assays (n = 108) were assessed. As expected, most of the SNPs (52/76) showed no biological implications. Moreover, this approach was applied to evaluate the putative synergy that could emerge when two mutations occurred in cis. In addition, we propose a putative pathogenic effect of five novel mutations, p.L107Q, p.L122R, p.R132H, p.P335L and p.H466fs, found in 21-hydroxylase deficient patients of our cohort. © The Author(s) 2016. Fil:Taboas, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Nadra, A.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_20452322_v6_n_p_Bruque |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
CYP21A2 protein, human steroid 21 monooxygenase chemistry computer simulation congenital adrenal hyperplasia genetic variation genetics human metabolism molecular model mutation protein conformation protein stability single nucleotide polymorphism structure activity relation Adrenal Hyperplasia, Congenital Computer Simulation Genetic Variation Humans Models, Molecular Mutation Polymorphism, Single Nucleotide Protein Conformation Protein Stability Steroid 21-Hydroxylase Structure-Activity Relationship |
| spellingShingle |
CYP21A2 protein, human steroid 21 monooxygenase chemistry computer simulation congenital adrenal hyperplasia genetic variation genetics human metabolism molecular model mutation protein conformation protein stability single nucleotide polymorphism structure activity relation Adrenal Hyperplasia, Congenital Computer Simulation Genetic Variation Humans Models, Molecular Mutation Polymorphism, Single Nucleotide Protein Conformation Protein Stability Steroid 21-Hydroxylase Structure-Activity Relationship Bruque, C.D. Delea, M. Fernández, C.S. Orza, J.V. Taboas, M. Buzzalino, N. Espeche, L.D. Solari, A. Luccerini, V. Alba, L. Nadra, A.D. Dain, L. Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations |
| topic_facet |
CYP21A2 protein, human steroid 21 monooxygenase chemistry computer simulation congenital adrenal hyperplasia genetic variation genetics human metabolism molecular model mutation protein conformation protein stability single nucleotide polymorphism structure activity relation Adrenal Hyperplasia, Congenital Computer Simulation Genetic Variation Humans Models, Molecular Mutation Polymorphism, Single Nucleotide Protein Conformation Protein Stability Steroid 21-Hydroxylase Structure-Activity Relationship |
| description |
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90-95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we initially classified all known mutants (n = 343) according to their putative functional impacts, which were either reported in the literature or inferred from structural models. We then performed a detailed analysis on the subset of mutations believed to exclusively impact protein stability. For those mutants, the predicted stability was calculated and correlated with the variant's expected activity. A high concordance was obtained when comparing our predictions with available in vitro residual activities and/or the patient's phenotype. The predicted stability and derived activity of all reported mutations and SNPs lacking functional assays (n = 108) were assessed. As expected, most of the SNPs (52/76) showed no biological implications. Moreover, this approach was applied to evaluate the putative synergy that could emerge when two mutations occurred in cis. In addition, we propose a putative pathogenic effect of five novel mutations, p.L107Q, p.L122R, p.R132H, p.P335L and p.H466fs, found in 21-hydroxylase deficient patients of our cohort. © The Author(s) 2016. |
| format |
JOUR |
| author |
Bruque, C.D. Delea, M. Fernández, C.S. Orza, J.V. Taboas, M. Buzzalino, N. Espeche, L.D. Solari, A. Luccerini, V. Alba, L. Nadra, A.D. Dain, L. |
| author_facet |
Bruque, C.D. Delea, M. Fernández, C.S. Orza, J.V. Taboas, M. Buzzalino, N. Espeche, L.D. Solari, A. Luccerini, V. Alba, L. Nadra, A.D. Dain, L. |
| author_sort |
Bruque, C.D. |
| title |
Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations |
| title_short |
Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations |
| title_full |
Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations |
| title_fullStr |
Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations |
| title_full_unstemmed |
Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations |
| title_sort |
structure-based activity prediction of cyp21a2 stability variants: a survey of available gene variations |
| url |
http://hdl.handle.net/20.500.12110/paper_20452322_v6_n_p_Bruque |
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