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Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Dec 28; Vol. 23 (1). Date of Electronic Publication: 2021 Dec 28. - Publication Year :
- 2021
-
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.
- Subjects :
- Adolescent
Amino Acid Sequence
Brazil
Child, Preschool
Computer Simulation
Conserved Sequence
Female
Humans
Infant
Kinetics
Male
Models, Molecular
Mutant Proteins chemistry
Mutant Proteins genetics
Portugal
Reproducibility of Results
Steroid 21-Hydroxylase chemistry
Genetics, Population
Mutation genetics
Steroid 21-Hydroxylase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 23
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 35008721
- Full Text :
- https://doi.org/10.3390/ijms23010296