| Full text | |
| Author(s): Show less - |
Karlsson, Leif
[1]
;
Michelatto, Debora de Paula
[1, 2]
;
Gori Lusa, Ana Leticia
[2]
;
Mgnani Silva, Camila D'Almeida
[3]
;
Ostberg, Linus J.
[4, 5]
;
Persson, Bengt
[6]
;
Guerra-Junior, Gil
[3]
;
Valente de Lemos-Marini, Sofia Helena
[3]
;
Baldazzi, Lilia
[7]
;
Menabo, Soara
[7]
;
Balsamo, Antonio
[7]
;
Greggio, Nella Augusta
[8]
;
de Mello, Maricilda Palandi
[2]
;
Barbaro, Michela
[9]
;
Lajic, Svetlana
[1]
Total Authors: 15
|
| Affiliation: | [1] Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit Q2 08, Stockholm - Sweden
[2] Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Lab Genet Mol Humana, Campinas, SP - Brazil
[3] Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP - Brazil
[4] Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm - Sweden
[5] Karolinska Inst, Dept Med Biochem & Biophys, eSSENCE, Stockholm - Sweden
[6] Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, Uppsala - Sweden
[7] S Orsola Malpighi Univ Hosp, Ctr Rare Endocrine Condit CARENDO BO Endo ERN, Dept Woman Child & Urologkal Dis, Bologna - Italy
[8] Dept Womens & Childrens Hlth Padua, Pediat Endocrinol Unit, Padua - Italy
[9] Karolinska Univ Hosp, Ctr Inherited Metab Dis CMMS L7 05, Karolinska Inst, Dept Mol Med & Surg, Stockholm - Sweden
Total Affiliations: 9
|
| Document type: | Journal article |
| Source: | CLINICAL BIOCHEMISTRY; v. 73, p. 50-56, NOV 2019. |
| Web of Science Citations: | 0 |
| Abstract | |
Objective: Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where > 90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.{[}Ile172Asn;Val358Ile], p.{[}Val281Leu;Arg369Gln], or p. {[}Asp377Tyr;Leu461Pro]) identified in patients with CAH. Methods: All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. Results: The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40-82%). An additive effect on the reduction of enzymatic activity (1-17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. Conclusions: Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH. (AU) | |
| FAPESP's process: | 14/09844-0 - Functional analyses of novel nucleotides variations in the CYP21A2 gene identified in patients with congenital adrenal hyperplasia |
| Grantee: | Débora de Paula Michelatto |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate (Direct) |
| FAPESP's process: | 12/16815-0 - Analysis of alterations in the gene expression and in the enzymatic activity resulting from CYP21A2 gene intronic and exonic variations |
| Grantee: | Débora de Paula Michelatto |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |