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Functional analyses of novel nucleotides variations in the CYP21A2 gene identified in patients with congenital adrenal hyperplasia

Grant number: 14/09844-0
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): September 01, 2014
Effective date (End): August 31, 2015
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Maricilda Palandi de Mello
Grantee:Débora de Paula Michelatto
Supervisor abroad: Svetlana Lajic
Home Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Karolinska Institutet, Sweden  
Associated to the scholarship:12/16815-0 - Analysis of alterations in the gene expression and in the enzymatic activity resulting from CYP21A2 gene intronic and exonic variations, BP.DD

Abstract

Congenital Adrenal Hyperplasia (CAH), one of the most frequent autosome recessive disorders, is caused by defects in steroidogenic enzymes involved in the cortisol biosynthesis. One consequence of this is the deviation to the synthesis of androgenic hormones. Intrauterine prenatal exposure to androgen excess in critical stages of sexual differentiation leads to external genitalia virilization of 46,XX fetus and can result in ambiguous genitalia at birth.Screening of CAH affected families in our research group identified novel mutations. To continue this study, the objective of this project is to analyze the functional role of five such mutations (p.Leu12Met; p.Arg16Cys; p.Asp377Tyr; p.Thr450Met; p.Leu461Pro), one novel in frame deletion (p.(Gln398_Ala391del)), one known mutation without in vitro studies (p.Ser202Gly) and one combination of novel mutations (p.Asp377Tyr+p.Leu461Pro) in CYP21A2 protein. The methodology for this study will include: expression of normal and mutants CYP21A2 gene, enzymatic activity assay, protein kinetics and Western blotting.Those techniques will be performed in the department of Molecular Medicine and Surgery at the Karolinska Institute, in Sweden. The responsible for the Inborn Errors of Endocrinology and Metabolism Group is Dr. Anna Wedell and the pediatrician/molecular biologist is Dr. Svetlana Lajic, who also develop research with CYP21A2 gene in patients with CAH and is part of one of the most respected researches group in the CAH studies in Europe. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
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; et al. Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY, . (14/09844-0, 12/16815-0)
KARLSSON, LEIF; MICHELATTO, DEBORA DE PAULA; GORI LUSA, ANA LETICIA; MGNANI SILVA, CAMILA D'ALMEIDA; OSTBERG, LINUS J.; PERSSON, BENGT; GUERRA-JUNIOR, GIL; VALENTE DE LEMOS-MARINI, SOFIA HELENA; BALDAZZI, LILIA; MENABO, SOARA; et al. Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia. CLINICAL BIOCHEMISTRY, v. 73, p. 50-56, . (14/09844-0, 12/16815-0)

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