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" (2016) Scientific Reports. 6
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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.


Documento: Artículo
Título:Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations
Autor: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.
Filiación:Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina
Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
Consultorio y Laboratorio de Genética, Rosario, Argentina
Departamento de Química Biológica Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina
Laboratorio de Cultivo Celular y Medicina Regenerativa, Servicio de Ortopedia y Traumatología, Hospital de Agudos Juan A. Fernández, Buenos Aires, Argentina
Palabras clave: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
Título revista:Scientific Reports
Título revista abreviado:Sci. Rep.
CAS:steroid 21 monooxygenase, 9029-68-9; CYP21A2 protein, human; Steroid 21-Hydroxylase


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---------- APA ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., Espeche, L.D.,..., Dain, L. (2016) . Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations. Scientific Reports, 6.
---------- CHICAGO ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., et al. "Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations" . Scientific Reports 6 (2016).
---------- MLA ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., et al. "Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations" . Scientific Reports, vol. 6, 2016.
---------- VANCOUVER ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., et al. Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations. Sci. Rep. 2016;6.