Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations
| Autor: | Mayara J. Prado, Shripriya Singh, Rodrigo Ligabue-Braun, Bruna V. Meneghetti, Thaiane Rispoli, Cristiane Kopacek, Karina Monteiro, Arnaldo Zaha, Maria L. R. Rossetti, Amit V. Pandey |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
Models Molecular Adolescent pediatrics QH301-705.5 610 Medicine & health 21-hydroxylase deficiency congenital adrenal hyperplasia CYP21A2 functional characterization Article Catalysis Inorganic Chemistry Humans Computer Simulation Amino Acid Sequence Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Conserved Sequence Spectroscopy Portugal Organic Chemistry Infant Reproducibility of Results General Medicine Computer Science Applications Kinetics Chemistry Genetics Population Child Preschool Mutation 570 Life sciences biology Female Mutant Proteins Steroid 21-Hydroxylase Brazil |
| Zdroj: | International Journal of Molecular Sciences, Vol 23, Iss 296, p 296 (2022) Prado, Mayara J.; Singh, Shripriya; Ligabue-Braun, Rodrigo; Meneghetti, Bruna V.; Rispoli, Thaiane; Kopacek, Cristiane; Monteiro, Karina; Zaha, Arnaldo; Rossetti, Maria L. R.; Pandey, Amit Vikram (2022). Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations. International journal of molecular sciences, 23(1), p. 296. MDPI 10.3390/ijms23010296 International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 23; Issue 1; Pages: 296 |
| ISSN: | 1661-6596 1422-0067 |
| DOI: | 10.3390/ijms23010296 |
| Popis: | Deficiency of Cytochrome P450 Steroid 21-hydroxylase (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction along with functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in the Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of 21OH deficiency. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|