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Analysis of the gonadotropin releasing hormone receptor gene (GNRHR): mutation frequency in the Brazilian population and founder effect of the p.R139H mutation

Grant number: 11/15530-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): March 01, 2012
Effective date (End): June 30, 2013
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Letícia Ferreira Gontijo Silveira
Grantee:Daiane Beneduzzi de Deus
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Congenital normosmic isolated hipogonadotropic hypogonadism (IHH) is caused by defects on the synthesis, secretion or action of GnRH. The most common genetic causes of IHH are inactivating mutations in the pituitary GnRH receptor (GnRHR). The first mutations in the GnRHR gene were described by de Roux et al. in 1997 and, since then, many other defects have been reported in this gene. Costa et al. (2001) studied the GNRHR gene in 14 Brazilian patients with normosmic HHI and identified for the first time the homozygous mutation p.R139H. Our group, at Laboratório de Hormônios e Genética Molecular LIM/42, has recently expanded the GNRHR study in patients with IHH normosmic and the p.R139H mutation was identified in three other patients, two of them familial (not published). Taking in consideration the frequency of the p.R139H mutation in the Brazilian population, this mutation may have a common ancestral. Recently Vaaralathi et al. (2011) studied the GNRHR gene in patients with constitutional delay of puberty and found a novel deletion (p.F309del) in one patient, absent in 200 normal controls. Based on these data, our aim is to analyze the frequency of mutations in the GNRHR gene with normosmic IHH and constitutional delay of puberty and to investigate a possible founder effect of the p.R139H mutation. Ninety four non related patients with normosmic IHH (69 males and 25 females), including 6 familial cases, and 51 patients with constitutional delay of puberty (42 boys and 9 girls) were selected for this study. The three exons of GNRHR will be amplified by PCR reaction from genomic DNA of the selected patients and automatically sequenced. To analyze the founder effect, tag SNPs will be selected by Haploview program. The DNA will be amplified with specific primers for the tag SNPs and the result will be analyzed by GeneScan. (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)
BENEDUZZI, DAIANE; TRARBACH, ERICKA B.; MIN, LE; JORGE, ALEXANDER A. L.; GARMES, HERALDO M.; RENK, ALESSANDRA COVALLERO; FICHNA, MARTA; FICHNA, PIOTR; ARANTES, KARINA A.; COSTA, ELAINE M. F.; et al. Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertility and Sterility, v. 102, n. 3, p. 838-U561, . (11/15530-0)
BENEDUZZI, DAIANE; TRARBACH, ERICKA B.; LATRONICO, ANA CLAUDIA; DE MENDONCA, BERENICE BILHARINHO; SILVEIRA, LETICIA F. G.. Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 56, n. 8, SI, p. 540-544, . (11/15530-0)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
DEUS, Daiane Beneduzzi de. Study of GNRHR gene in isolated hypogonadotropic hypogonadism and constitutional delay of growth and puberty. 2013. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.

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