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
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders |
UniBE Contributor: |
Pandey, Amit Vikram |
Subjects: |
600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology |
ISSN: |
1422-0067 |
Publisher: |
MDPI |
Funders: |
[73] Swiss Government Excellence Scholarship |
Language: |
English |
Submitter: |
Amit Vikram Pandey |
Date Deposited: |
07 Feb 2022 09:07 |
Last Modified: |
12 Jan 2023 13:01 |
Publisher DOI: |
10.3390/ijms23010296 |
PubMed ID: |
35008721 |
Uncontrolled Keywords: |
CYP21A2, Cytochrome P450, Brazil, Congenital adrenal hyperplasia |
BORIS DOI: |
10.48350/164605 |
URI: |
https://boris.unibe.ch/id/eprint/164605 |
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