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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia

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Autor(es):
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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]
Número total de Autores: 15
Afiliação do(s) autor(es):
[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
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: CLINICAL BIOCHEMISTRY; v. 73, p. 50-56, NOV 2019.
Citações Web of Science: 0
Resumo

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)

Processo FAPESP: 14/09844-0 - Análise funcional de novas variações nucleotídicas no gene CYP21A2 identificadas em pacientes com hiperplasia da adrenal congênita
Beneficiário:Débora de Paula Michelatto
Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
Processo FAPESP: 11/51808-2 - Estudo da expressao do gene cyp21a2 e da atividade enzimatica da 21-hidroxilase resultante de mutacoes raras em casos de hyperplasia da adrenal congenita nas formas classica e tardia.
Beneficiário:Maricilda Palandi de Mello
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 12/16815-0 - Análise de alterações na expressão gênica e na atividade enzimática resultantes de variações intrônicas e exônicas no gene CYP21A2
Beneficiário:Débora de Paula Michelatto
Modalidade de apoio: Bolsas no Brasil - Doutorado Direto