Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations

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

[img]
Preview
Text
ijms-23-00296.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (3MB) | Preview

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)

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

Actions (login required)

Edit item Edit item
Provide Feedback