title: Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations.
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.
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.|Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bruque
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Marisol
authors.initials: M
authors.lastname: Delea
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Fernández
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Juan V
authors.initials: JV
authors.lastname: Orza
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Melisa
authors.initials: M
authors.lastname: Taboas
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Noemí
authors.initials: N
authors.lastname: Buzzalino
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Lucía D
authors.initials: LD
authors.lastname: Espeche
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Andrea
authors.initials: A
authors.lastname: Solari
authors.affiliation: Consultorio y Laboratorio de Genética, Rosario, Argentina.
authors.forename: Verónica
authors.initials: V
authors.lastname: Luccerini
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
authors.forename: Liliana
authors.initials: L
authors.lastname: Alba
authors.affiliation: Departamento de Química Biológica Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Nadra
authors.affiliation: Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.|Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: Liliana
authors.initials: L
authors.lastname: Dain
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D003198:Computer Simulation; D014644:Genetic Variation; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D055550:Protein Stability; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase