Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations

International Journal of Molecular Sciences

Rodrigo Ligabue-Braun¹  Shripriya Singh²  Amit V. Pandey²  Maria L. R. Rossetti³  Bruna V. Meneghetti³  Thaiane Rispoli³  Arnaldo Zaha³  Karina Monteiro³  Mayara J. Prado³  Cristiane Kopacek⁴ 

[1] Departament of Pharmacosciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-170, Brazil;Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland;Graduate Program in Cell and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91501-970, Brazil;Serviço de Referência em Triagem Neonatal, Hospital Materno Infantil Presidente Vargas, Porto Alegre 90035-074, Brazil;

关键词: 21-hydroxylase deficiency;    congenital adrenal hyperplasia;    CYP21A2;    functional characterization;   

DOI  :  10.3390/ijms23010296

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown