Please use this identifier to cite or link to this item: http://sgc.anlis.gob.ar/handle/123456789/1802
Title: Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations
Authors: Bruque, Carlos D 
Delea, Marisol 
Fernández, Cecilia 
Orza, Juan V 
Taboas, Melisa 
Buzzalino, Noemí 
Espeche, Lucía 
Solari, Andrea 
Luccerini, Verónica 
Alba, Liliana 
Nadra, Alejandro D. 
Dain, Liliana 
Keywords: Anomalías Congénitas;Hiperplasia Suprarrenal Congénita
Issue Date: Dec-2016
Publisher: Nature Research
Journal: Scientific reports 
Abstract: 
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.
Description: 
Fil: Bruque, Carlos D. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Delea, Marisol. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Fernández, Cecilia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Orza, Juan V. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Taboas, Melisa. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Espeche, Lucía. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Solari, Andrea. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Luccerini, Verónica. Consultorio y Laboratorio de Genética, Rosario, Argentina.

Fil: Alba, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.

Fil: Nadra, Alejandro D. Departamento de Química Biológica Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET; Argentina.

Fil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
URI: http://sgc.anlis.gob.ar/handle/123456789/1802
ISSN: 2045-2322
DOI: 10.1038/srep39082
Rights: Open Access
Creative Commons Attribution 4.0 International License
Appears in Collections:Publicaciones CeNaGeM

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