Faculty Opinions recommendation of Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54.

Abstract Context: Loss of function of the G protein-coupled receptor of kisspeptins (GPR54) was recently described as a new cause of isolated hypogonadotropic hypogonadism. In vivo studies performed in several species have confirmed the major role of kisspeptins in neuroendocrine regulation of the gonadotropic axis and therefore sexual maturation. Objective: The objective of this study was to specify the exact contribution of kisspeptins and GPR54 to the initiation of puberty in humans. Design: Detailed neuroendocrine descriptions were performed in five patients with isolated hypogonadotropic hypogonadism bearing a new GPR54-inactivating mutation. Results: A homozygous mutation (T305C) leading to a leucine substitution with proline (L102P) was found in the five affected patients. This substitution completely inhibited GPR54 signaling. Phenotypic analysis revealed variable expressivity in the same family, either partial or complete gonadotropic deficiency. LH pulsatility analysis showed peaks with normal frequency but low amplitude. Repeated GnRH tests performed between 12 and 21 yr of age in one affected male revealed progressive changes in pituitary response from an early pubertal to an almost full pubertal pattern. Double GnRH test stimulations performed at a 120-min interval showed reduced dynamic pituitary response in GPR54-mutated patients. Conclusion: GPR54 inactivation does not impede neuroendocrine onset of puberty; rather, it delays and slows down pubertal maturation of the gonadotropic axis. The L102P loss of function mutation in GPR54 results in a more quantitative than qualitative defect of gonadotropic axis activation.

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

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302012000800013 ◽

2012 ◽

Vol 56 (8) ◽

pp. 540-544 ◽

Cited By ~ 5

Author(s):

Daiane Beneduzzi ◽

Ericka B. Trarbach ◽

Ana Claudia Latronico ◽

Berenice Bilharinho de Mendonca ◽

Letícia F. G. Silveira

Keyword(s):

In Silico ◽

Novel Mutation ◽

Hypogonadotropic Hypogonadism ◽

In Silico Analysis ◽

Control Group ◽

Coding Region ◽

Novel Variant ◽

Gonadotropin Releasing Hormone Receptor ◽

Inactivating Mutation ◽

Silico Analysis

We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4

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Complete Hypogonadotropic Hypogonadism Associated with a Novel Inactivating Mutation of the Gonadotropin-Releasing Hormone Receptor

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.84.10.3811 ◽

1999 ◽

Vol 84 (10) ◽

pp. 3811-3816 ◽

Cited By ~ 22

Author(s):

F. P. Pralong

Keyword(s):

Hormone Receptor ◽

Hypogonadotropic Hypogonadism ◽

Gonadotropin Releasing Hormone ◽

Releasing Hormone ◽

Gonadotropin Releasing Hormone Receptor ◽

Inactivating Mutation

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An Isolated Hypogonadotropic Hypogonadism due to a L102P Inactivating Mutation of KISS1R/GPR54 in a Large Family

Case Reports in Pediatrics ◽

10.1155/2019/3814525 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6

Author(s):

Ahmad J. Alzahrani ◽

Azzam Ahmad ◽

Tariq Alhazmi ◽

Lujin Ahmad

Keyword(s):

Amino Acid ◽

Extended Family ◽

Hypogonadotropic Hypogonadism ◽

Large Family ◽

Homozygous Mutation ◽

Loss Of Function ◽

Gonadotropin Secretion ◽

Healthy Baby ◽

Inactivating Mutation

KISS1R (GPR54) mutations have been reported in several patients with congenital normosmic idiopathic hypogonadotropic hypogonadism (nIHH). We aim to describe in detail nIHH patients with KISS1R (GPR54) mutations belonging to one related extended family and to review the literature. A homozygous mutation (T305C) leading to a leucine substitution with proline (L102P) was found in three affected kindred (2 males and 1 female) from a consanguineous Saudi Arabian family. This residue is localized within the first exoloop of the receptor, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs its function. In the affected female, a combined gonadotropin administration restored regular period and ovulation and she conceived with a healthy baby boy after 4 years of marriage. We showed that a loss-of-function mutation (p.Tyr305C) in the KISS1R gene can cause (L102P) KISS1 receptor dysfunction and familial nIHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of periods and later on pregnancy by an exogenous gonadotropin administration further support, in humans, that the KISS1R mutation has no other harmful effects on the patients apart from the gonadotropin secretion impairment.

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Complete Hypogonadotropic Hypogonadism Associated with a Novel Inactivating Mutation of the Gonadotropin-Releasing Hormone Receptor1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.10.6042 ◽

1999 ◽

Vol 84 (10) ◽

pp. 3811-3816

Author(s):

François P. Pralong ◽

Fulgencio Gomez ◽

Einar Castillo ◽

Susanna Cotecchia ◽

Liliane Abuin ◽

...

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Gonadotropin Releasing Hormone ◽

Releasing Hormone ◽

Inactivating Mutation

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PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency

Acta Endocrinologica ◽

10.1530/eje-12-0578 ◽

2013 ◽

Vol 168 (1) ◽

pp. 31-37 ◽

Cited By ~ 16

Author(s):

Antoine Moya-Plana ◽

Carine Villanueva ◽

Ollivier Laccourreye ◽

Pierre Bonfils ◽

Nicolas de Roux

Keyword(s):

Olfactory Bulb ◽

Hypogonadotropic Hypogonadism ◽

Incomplete Penetrance ◽

Neuron Development ◽

Phenotype Analysis ◽

History Of ◽

Rare Phenotype ◽

Gene Defects ◽

Design And Methods ◽

Considerable Complexity

ObjectiveIsolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders.Design and methodsIn 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced.ResultsThree PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations.ConclusionsThis study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans.

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