Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations

dc.creatorBruque, Carlos D
dc.creatorDelea, Marisol
dc.creatorFernández, Cecilia
dc.creatorOrza, Juan V
dc.creatorTaboas, Melisa
dc.creatorBuzzalino, Noemí
dc.creatorEspeche, Lucía
dc.creatorSolari, Andrea
dc.creatorLuccerini, Verónica
dc.creatorAlba, Liliana
dc.creatorNadra, Alejandro D.
dc.creatorDain, Liliana
dc.date2020-12-02T14:31:08Z
dc.date2020-12-02T14:31:08Z
dc.date2016-12
dc.date.accessioned2023-08-29T20:07:30Z
dc.date.available2023-08-29T20:07:30Z
dc.identifier2045-2322
dc.identifierhttp://sgc.anlis.gob.ar/handle/123456789/1802
dc.identifier10.1038/srep39082
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8519688
dc.descriptionFil: Bruque, Carlos D. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Delea, Marisol. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Fernández, Cecilia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Orza, Juan V. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Taboas, Melisa. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Espeche, Lucía. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Solari, Andrea. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Luccerini, Verónica. Consultorio y Laboratorio de Genética, Rosario, Argentina.
dc.descriptionFil: Alba, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionFil: Nadra, Alejandro D. Departamento de Química Biológica Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET; Argentina.
dc.descriptionFil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
dc.descriptionCongenital 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.
dc.formatpdf
dc.languageen
dc.publisherNature Research
dc.relationScientific reports
dc.rightsopen
dc.sourceScientific Reports 2016; 6:39082
dc.subjectAnomalías Congénitas
dc.subjectHiperplasia Suprarrenal Congénita
dc.titleStructure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations
dc.typeArtículo


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