Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations

DOI
Official URL
Publisher DOI
PubMed ID
35008721
Abstract
Deficiency of 21-hydroxylase enzyme (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction and 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 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 CYP21A2 deficiency.
Date Issued
2022-01-10
Publication Type
Article
Subject(s)
Subjects
CYP21A2
•
Cytochrome P450
•
Brazil
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Congenital adrenal hyperplasia
Language(s)
en
Author(s)
Prado, Mayara J.
Singh, Shripriya
Ligabue-Braun, Rodrigo
Meneghetti, Bruna V.
Rispoli, Thaiane
Kopacek, Cristiane
Monteiro, Karina
Zaha, Arnaldo
Rossetti, Maria L. R.
Additional Credits
Journal
International journal of molecular sciences
Publisher
MDPI
ISSN
1422-0067
Access(Rights)
open.access
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