A Prevalent GNRHR Mutation with Founder Effect in Brazilian Patients with Normosmic Isolated Hypogonadotropic Hypogonadism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 596-621-Pediatric Endocrinology /Steroids and Puberty
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-610
Daiane Beneduzzi de Deus1, Ericka Barbosa Trarbach2, Elaine Maria Frade Costa1, Marta Fichna3, Piotr Fichna4, Berenice Bilharinho Mendonca5, Ana Claudia Latronico2 and Leticia Gontijo Silveira*2
1Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil, 2Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil, 3Poznan University of Medical Sciences, Poznan, Poland, 4University of Medical Sciences, Poznan, Poland, 5Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Context: GnRH receptor (GNRHR) inactivating mutations are the most common genetic cause of normosmic congenital isolated hypogonadotropic hypogonadism (nIHH). A variety of GNRHR mutations distributed along the whole protein has been reported in patients with sporadic or familial forms of nIHH. Although there are no recognized hotspots, recurrence of some rare variants has been reported. The p.R139H mutation is particularly prevalent in the Brazilian population, having been identified in four unrelated kindreds. This mutation has also been found in six other unrelated patients from different geographic locations worldwide.

Aim:To determine de cause of the recurrence of GNRHR p.R139H mutation in patients with nIHH, i.e. a common ancestor (“founder” mutation) or hotspot mutation region.

Patients and methods: Haplotype analyses of three polymorphic microsatellite markers D4S409, D4S3018, D4S2387 flanking GNRHRgene was performed in four nIHH Brazilian patients, 2 sporadic and 2 familial cases, and one previously reported Polish family, all of them carrying the p.R139H mutation. Haplotype mapping was also performed in the probands relatives and in a control group composed of 50 individuals with normal pubertal development.

Results: Although these Brazilian patients did not refer to be related, a detailed interview revealed that all of them had ancestors originating from the same region in the Northeast of Brazil (Itabaiana-SE). All the p.R139H affected Brazilian patients presented the same haplotype (294,259,216). In the control population, this haplotype was found in 4% of the subjects. On the other hand, affected Polish family presented with a different haplotype (278,256,217).

Conclusion: These results suggest that the p.R139H mutation has a common ancestor in the Brazilian population. However, the presence of a different haplotype in the Polish patient opens the possibility that R139 could be considered a hotspot mutation region.

Nothing to Disclose: DBD, EBT, EMFC, MF, PF, BBM, ACL, LGS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Financial support: FAPESP grant 2011/15530-0