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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects

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Michelatto, Debora de Paula ; Karlsson, Leif ; Gori Lusa, Ana Leticia ; Mgnani Silva, Camila D'Almeida ; Ostberg, Linus Joakim ; Persson, Bengt ; Guerra-Junior, Gil ; Valente de Lemos-Marini, Sofia Helena ; Barbaro, Michela ; de Mello, Maricilda Palandi ; Lajic, Svetlana
Total Authors: 11
Document type: Journal article
Web of Science Citations: 3

We present the functional and structural effects of seven novel (p.Leu12Met, p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, p.Gln389 Ala391del, and p.Thr450Met) and two previously reported but not studied (p.Ser113Phe and p.Thr450Pro) CYP21A2 mutations. Functional analyses were complemented with in silico prediction of mutation pathogenicity based on the recently crystallized human CYP21A2 structure. Mutated proteins were transiently expressed in COS-1 cells and enzyme activities towards 17-hydroxyprogesterone and progesterone were determined. Residual enzyme activities between 43% and 97% were obtained for p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met, similar to the activities of the well-known nonclassic mutations p.Pro453Ser and p.Pro482Ser, whereas the p.Leu12Met variant showed an activity of 100%. Conversely, the novel p.Ser113Phe, p. Gln389 Ala391del, and p.Thr450Promutations drastically reduced the enzyme function below 4%. The K-m values for all novel variants were in the same order of magnitude as for the wild-type protein except for p.The450Met. The maximum velocity was decreased for all mutants except for p.Leu12Met. We conclude that p. Leu12Met is a normal variant; the mutations p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met could be associated with very mild nonclassic CAH, and the mutations p.Ser113Phe, p.Gln389 Ala391del, and p.Thr450Pro are associated with classic CAH. The obtained residual activities indicated a good genotype-phenotype correlation. (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)