Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism

Beneduzzi, Daiane; Trarbach, Ericka Barbosa; Latrônico, Ana Claudia; Mendonca, Berenice B.; Silveira, Letícia Ferreira Gontijo

doi:10.1590/s0004-27302012000800013

Cited by 8 publications

(4 citation statements)

References 12 publications

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“…The GNRHR missense mutations identified in this study have been previously reported in other nCHH patients, namely p.Gln106Arg (3), p.Val134Gly (12), p.Arg139Cys (13), p.Arg262Gln (3) and p.Tyr283His (14). In vitro functional studies have demonstrated that these mutated receptors result in either reduced ligand affinity, reduced signal transduction or abolished plasma membrane expression (3, 12, 13).…”

Section: Discussionsupporting

confidence: 72%

GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism

Gonçalves

Aragüés

Bastos

et al. 2017

Endocrine Connections

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ObjectiveNormosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH) and, unlike Kallmann syndrome, is associated with a normal sense of smell. Mutations in the GNRHR gene cause autosomal recessive nCHH. The aim of this study was to determine the prevalence of GNRHR mutations in a group of 40 patients with nCHH.DesignCross-sectional study of 40 unrelated patients with nCHH.MethodsPatients were screened for mutations in the GNRHR gene by DNA sequencing.ResultsGNRHR mutations were identified in five of 40 patients studied. Four patients had biallelic mutations (including a novel frameshift deletion p.Phe313Metfs*3, in two families) in agreement with autosomal recessive inheritance. One patient had a heterozygous GNRHR mutation associated with a heterozygous PROKR2 mutation, thus suggesting a possible role of synergistic heterozygosity in the pathogenesis of the disorder.ConclusionsThis study further expands the spectrum of known genetic defects associated with nCHH. Although GNRHR mutations are usually biallelic and inherited in an autosomal recessive manner, the presence of a monoallelic mutation in a patient should raise the possibility of a digenic/oligogenic cause of nCHH.

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Section: Discussionsupporting

confidence: 72%

GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism

Gonçalves

Aragüés

Bastos

et al. 2017

Endocrine Connections

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“…PCR products were purified and automatically sequenced in an ABI Prism Genetic Analyzer 3100 (Perkin- Elmer, Foster City, CA, USA) (26). …”

Section: Methodsmentioning

confidence: 99%

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

Beneduzzi

Trarbach

Min

et al. 2014

Fertility and Sterility

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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) 110 individuals with normosmic IHH (74 males) and 50 with CGDP. 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 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.

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“…Interestingly, this receptor does not have a carboxy-terminal cytoplasmic tail, thus, it internalizes relatively slowly and it does not rapidly desensitize [58]. Inactivating mutations of GNRHR were the first to be recognized as monogenic causes of CHH condition [64]. Null GNRHR mice models display a similar phenotype to human CHH [1].…”

Section: Genetic Basis Of Chhmentioning

confidence: 99%

“…Over 22 human GNRHR inactivating mutations, with no hotspot, were described [63] and these different genotypes result in a wide phenotypic spectrum, ranging from fertile eunuch syndrome and partial hypogonadotropic hypogonadism to the most complete form of GnRH resistance, characterized by cryptorchidism, micropenis, undetectable gonadotropins and the absence of pubertal development [1]. Although many defects in a large number of different genes were associated to CHH, GNRHR is still the most commonly affected gene in this pathogenic condition [64]. Since the vast majority of patients harbouring GNRHR mutations are resistant to GnRH, the effective fertility treatment is achieved with gonadotropins [63].…”

Section: Genetic Basis Of Chhmentioning

confidence: 99%

Central Hypogonadotropic Hypogonadism: Genetic Complexity of a Complex Disease

Marino

Moriondo

Vighi

et al. 2014

International Journal of Endocrinology

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Central hypogonadotropic hypogonadism (CHH) is an emerging pathological condition frequently associated with overweight, metabolic syndrome, diabetes, and midline defects. The genetic mechanisms involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying CHH, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases. Indeed, all detected gene variants may explain a small proportion of the affected patients (43%), indicating that other genes or epigenetic mechanisms are involved in the onset of CHH. The aim of this review is to summarize the current knowledge on genetic background of CHH, organizing the large amount of data present in the literature in a clear and concise manner, to produce a useful guide available for researchers and clinicians.

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Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism

Cited by 8 publications

References 12 publications

GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism

GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism

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

Central Hypogonadotropic Hypogonadism: Genetic Complexity of a Complex Disease

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