scholarly journals Faculty Opinions recommendation of Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

2019 ◽  
Author(s):  
Aldo E Calogero ◽  
Rossella Cannarella
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
And Function

scholarly journals Author response: Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism

2019 ◽  
Author(s):  
Samuel Andrew Malone ◽  
Georgios E Papadakis ◽  
Andrea Messina ◽  
Nour El Houda Mimouni ◽  
Sara Trova ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Author Response ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
And Function

scholarly journals Clinical Manifestations of Impaired GnRH Neuron Development and Function

Neurosignals ◽  
2008 ◽  
Vol 16 (2-3) ◽  
pp. 165-182 ◽  
Author(s):  
Hyung-Goo Kim ◽  
Balasubramanian Bhagavath ◽  
Lawrence C. Layman
Keyword(s):  
Clinical Manifestations ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
And Function

scholarly journals Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Samuel Andrew Malone ◽  
Georgios E Papadakis ◽  
Andrea Messina ◽  
Nour El Houda Mimouni ◽  
Sara Trova ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Abnormal Development ◽  
Loss Of Function ◽  
Neuron Development ◽  
Motility Factor ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Whole Exome ◽  
Gnrh Neurons ◽  
And Function ◽  
Deficient Mice

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.

scholarly journals Defects in GnRH Neuron Migration/Development and Hypothalamic-Pituitary Signaling Impact Clinical Variability of Kallmann Syndrome

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 868
Author(s):  
Małgorzata Kałużna ◽  
Bartłomiej Budny ◽  
Michał Rabijewski ◽  
Jarosław Kałużny ◽  
Agnieszka Dubiel ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Gene Panel ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Pituitary Development ◽  
Targeted Ngs ◽  
Uncertain Significance ◽  
Next Generation Sequencing Ngs

Kallmann syndrome (KS) is a combination of isolated hypogonadotropic hypogonadism (IHH) with olfactory dysfunction, representing a heterogeneous disorder with a broad phenotypic spectrum. The genetic background of KS has not yet been fully established. This study was conducted on 46 Polish KS subjects (41 males, 5 females; average age: 29 years old). The studied KS patients were screened for defects in a 38-gene panel with next-generation sequencing (NGS) technology. The analysis revealed 27 pathogenic and likely pathogenic (P/LP) variants, and 21 variants of uncertain significance (VUS). The P/LP variants were detected in 20 patients (43.5%). The prevalence of oligogenic P/LP defects in selected genes among KS patients was 26% (12/46), whereas the co-occurrence of other variants was detected in 43% (20 probands). The examined KS patients showed substantial genotypic and phenotypic variability. A marked difference in non-reproductive phenotypes, involving defects in genes responsible for GnRH neuron development/migration and genes contributing to pituitary development and signaling, was observed. A comprehensive gene panel for IHH testing enabled the detection of clinically relevant variants in the majority of KS patients, which makes targeted NGS an effective molecular tool. The significance of oligogenicity and the high incidence of alterations in selected genes should be further elucidated.

scholarly journals The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

2021 ◽  
Vol 22 (17) ◽  
pp. 9425
Author(s):  
Roberto Oleari ◽  
Valentina Massa ◽  
Anna Cariboni ◽  
Antonella Lettieri
Keyword(s):  
Phenotypic Variability ◽  
Hypogonadotropic Hypogonadism ◽  
Neuroendocrine Cells ◽  
Delayed Puberty ◽  
Neuronal System ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Gnrh Neurons ◽  
Genes Encoding ◽  
Functional Relevance

Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.

scholarly journals DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development

2017 ◽  
Vol 27 (2) ◽  
pp. 359-372 ◽  
Author(s):  
Justine Bouilly ◽  
Andrea Messina ◽  
Georgios Papadakis ◽  
Daniele Cassatella ◽  
Cheng Xu ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Congenital Hypogonadotropic Hypogonadism

scholarly journals Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea

2020 ◽  
Author(s):  
Angela Delaney ◽  
Adam B Burkholder ◽  
Christopher A Lavender ◽  
Lacey Plummer ◽  
Veronica Mericq ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Sequence Variants ◽  
Hypothalamic Amenorrhea ◽  
Individual Susceptibility ◽  
The Face ◽  
Stress Variability ◽  
And Function ◽  
And Control ◽  
Previous Identification ◽  
Rare Sequence

Abstract Context Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. Objective We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. Design We compared patients with HA to control women. Setting The study was conducted at secondary referral centers. Patients and Other Participants Women with HA (n = 106) and control women (ClinSeq study; n = 468). Interventions We performed exome sequencing in all patients and controls. Main Outcome Measure(s) The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. Results RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). Conclusions Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

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