Inhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients

dc.creatorSoardi, FC
dc.creatorBarbaro, M
dc.creatorLau, IF
dc.creatorLemos-Marini, SHV
dc.creatorBaptista, MTM
dc.creatorGuerra-Junior, G
dc.creatorWedell, A
dc.creatorLajic, S
dc.creatorde Mello, MP
dc.date2008
dc.dateJUN
dc.date2014-11-18T13:13:30Z
dc.date2015-11-26T17:50:31Z
dc.date2014-11-18T13:13:30Z
dc.date2015-11-26T17:50:31Z
dc.date.accessioned2018-03-29T00:33:45Z
dc.date.available2018-03-29T00:33:45Z
dc.identifierJournal Of Clinical Endocrinology & Metabolism. Endocrine Soc, v. 93, n. 6, n. 2416, n. 2420, 2008.
dc.identifier0021-972X
dc.identifierWOS:000256507900058
dc.identifier10.1210/jc.2007-2594
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/80573
dc.identifierhttp://www.repositorio.unicamp.br/handle/REPOSIP/80573
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/80573
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1289702
dc.descriptionBackground: Most patients with 21-hydroxylase deficiency carry CYP21A1P-derived mutations, but an increasing number of novel and rare mutations have been reported in disease-causing alleles. Objective: Functional effects of three novel (p.G56R, p.L107R, p.L142P) and one recurrent (p.R408C) CYP21A2 mutations were investigated. The degree of enzyme impairment caused by p.H62L alone or combined to p.P453S was also analyzed. Design: The study included 10 Brazilian and two Scandinavian patients. To determine the deleterious role of each mutant protein, in vitro assays were performed in transiently transfected COS-1 cells. For a correct genotype-phenotype correlation, the enzymatic activities were evaluated toward the two natural substrates, 17-hydroxyprogesterone and progesterone. Results: Low levels of residual activities obtained for p.G56R, p.L107R, p.L142P, and p.R408C mutants classified them as classical congenital adrenal hyperplasia mutations, whereas the p.H62L showed an activity within the range of nonclassical mutations. Apparent kinetic constants for p.H62L confirmed the nonclassical classification as the substrate binding capacity was within the same magnitude for mutant and normal enzymes. A synergistic effect was observed for the allele bearing the p.H62L + p.P453S combination because it caused a significant reduction in the enzymatic activity. Conclusions: We describe the functional analysis of five rare missense mutations identified in Brazilian and Scandinavian patients. The p.G56R, p.L107R, and p.L142P are reported for the first time. Most probably these novel mutations are closer to null than the p.I172N, but for the p.G56R, that might not be the case, and the p.H62L is definitely a nonclassical mutation.
dc.descriptionO TEXTO COMPLETO DESTE ARTIGO, ESTARÁ DISPONÍVEL À PARTIR DE FEVEREIRO DE 2015.
dc.description93
dc.description6
dc.description2416
dc.description2420
dc.languageen
dc.publisherEndocrine Soc
dc.publisherChevy Chase
dc.publisherEUA
dc.relationJournal Of Clinical Endocrinology & Metabolism
dc.relationJ. Clin. Endocrinol. Metab.
dc.rightsembargo
dc.sourceWeb of Science
dc.subjectCongenital Adrenal-hyperplasia
dc.subjectSteroid 21-hydroxylase Deficiency
dc.subjectCytochrome P4502c5
dc.subjectClassical Form
dc.subjectGene
dc.subjectComplement
dc.subjectComponent
dc.subjectFeatures
dc.subjectCluster
dc.titleInhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients
dc.typeArtículos de revistas


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