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

Abstract

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)