Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects
| Autor: | Svetlana Lajic, Ana Letícia Gori Lusa, Sofia Helena Valente de Lemos-Marini, Linus J. Östberg, Michela Barbaro, Maricilda Palandi de Mello, Leif Karlsson, Gil Guerra-Júnior, Bengt Persson, Débora de Paula Michelatto, Camila D.Almeida Mgnani Silva |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Genetics Mutation lcsh:RC648-665 Enzyme function Article Subject Endocrine and Autonomic Systems Endocrinology Diabetes and Metabolism In silico Mutant 030209 endocrinology & metabolism Biology medicine.disease_cause Pathogenicity lcsh:Diseases of the endocrine glands. Clinical endocrinology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology Enzyme chemistry medicine |
| Zdroj: | International Journal of Endocrinology, Vol 2016 (2016) |
| ISSN: | 1687-8337 |
| DOI: | 10.1155/2016/4209670 |
| Popis: | 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)CYP21A2mutations. Functional analyses were complemented within silicoprediction 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.Thr450Pro mutations drastically reduced the enzyme function below 4%. TheKmvalues 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. |
| Databáze: | OpenAIRE |
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