Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Sep;102(3):838-846.e2.
doi: 10.1016/j.fertnstert.2014.05.044. Epub 2014 Jul 10.

Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay

Daiane Beneduzzi  1 , Ericka B Trarbach  2 , Le Min  3 , Alexander A L Jorge  4 , Heraldo M Garmes  5 , Alessandra Covallero Renk  6 , Marta Fichna  7 , Piotr Fichna  8 , Karina A Arantes  4 , Elaine M F Costa  1 , Anna Zhang  3 , Oluwaseun Adeola  3 , Junping Wen  3 , Rona S Carroll  3 , Berenice B Mendonça  1 , Ursula B Kaiser  3 , Ana Claudia Latronico  1 , Letícia F G Silveira  9
Affiliations

Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay

Daiane Beneduzzi et al. Fertil Steril. 2014 Sep.

Abstract

Objective: To analyze the GNRHR in patients with normosmic isolated hypogonadotropic hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP).

Design: Molecular analysis and in vitro experiments correlated with phenotype.

Setting: Academic medical center.

Patient(s): A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP.

Intervention(s): GNRHR coding region was amplified and sequenced.

Main outcome measure(s): Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect.

Result(s): Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic.

Conclusion(s): GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP.

Keywords: GnRH receptor; founder effect; hypogonadotropic hypogonadism; mutation; pubertal delay.

PubMed Disclaimer

Figures

Figure 1
Figure 1. GnRH stimulation of inositol phosphate (IP) accumulation by wild type (WT), V134G, and Y283H mutant GnRHR
COS-7 cells were transiently transfected with WT, V134G, or Y283H GnRHR as indicated. GnRH-stimulated IP accumulation was measured following stimulation with increasing concentrations of GnRH. Data points represent the mean ± SEM of triplicate samples and are presented as the percentage of the maximum response. *, P<0.05; ***, P<0.001 compared to WT GnRHR. The results shown are from a representative of three independent experiments.
Figure 2
Figure 2
(A) Schematic representation of the location of the microsatellite markers in relation to the GNRHR gene on chromosome 4. *Distance from the marker to GNRHR. (B) Pedigrees of the families carrying the p.R139H mutation and showing haplotypes obtained by microsatellite analysis. Pedigrees A, B, C and D: Brazilian families; Pedigree E: Polish family.
Figure 2
Figure 2
(A) Schematic representation of the location of the microsatellite markers in relation to the GNRHR gene on chromosome 4. *Distance from the marker to GNRHR. (B) Pedigrees of the families carrying the p.R139H mutation and showing haplotypes obtained by microsatellite analysis. Pedigrees A, B, C and D: Brazilian families; Pedigree E: Polish family.
See this image and copyright information in PMC

References

    1. Palmert MR, Boepple PA. Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab. 2001;86(6):2364–8. - PubMed
    1. Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012;366(5):443–53. Epub 2012/02/03. - PubMed
    1. Seminara SB, Hayes FJ, Crowley WF., Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev. 1998;19(5):521–39. - PubMed
    1. Quinton R, Duke VM, Robertson A, Kirk JM, Matfin G, de Zoysa PA, et al. Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol (Oxf) 2001;55(2):163–74. - PubMed
    1. de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997;337(22):1597–602. - PubMed

Publication types

Substances