Genetic variants of gonadotrophins and their receptors: Impact on the diagnosis and management of the infertile patient

Rivero-Müller, Adolfo; Huhtaniemi, Ilpo

doi:10.1016/j.beem.2021.101596

Cited by 14 publications

(5 citation statements)

References 118 publications

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“…Nonetheless, similarly to the mutations affecting LHCGR gene, these mutations are associated with a wide range of symptoms such as delayed puberty, hypogonadotropic hypogonadism and infertility in men as well as secondary amenorrhea and infertility in women 4 . Most often, aforementioned mutations result in impaired biosynthesis, abnormal posttranslational modification, incorrect heterodimerization with common subunit, impaired secretion of the hormone and its binding with receptor 41 . Moreover, we show that binding- and activation-assays can be run on the same samples, what saves time and money, and generates data with enhanced kinetics.…”

Section: Discussionmentioning

confidence: 99%

Glycoprotein-glycoprotein receptor binding detection using bioluminescence resonance energy transfer (BRET)

Adamczuk

Rivero-Müller

2023

Preprint

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The glycoprotein receptors, members of the large G protein-coupled receptors (GPCRs) family, are characterized by a large extracellular domains responsible of binding their glycoprotein hormones. Hormone-receptor interactions are traditionally analyzed by ligand-binding assays most often using radiolabeling but also by thermal shift assays. However, the use of radioisotopes requires appropriate laboratory conditions, and moreover, for this purpose, purified cell membranes are most often used instead of living cells. This in turn poses another challenge due to the altered stability of membrane proteins in detergents used for purification. Here, we overcome such limitations by applying bioluminescence resonance energy transfer (BRET) in living cells to determine hormone-receptor interactions between a Gaussia luciferase (Gluc) luteinizing hormone/chorionic gonadotropin receptor (LHCGR) fusion and its ligands (yoked human chorionic gonadotropin (yhCG) or luteinizing hormone (LH)) fused to the enhanced green fluorescent protein (eGFP). We first show that the Gluc-LHCGR is expressed on the plasma membrane and is fully functional, as well as the chimeric eGFP-hormones that are properly secreted and able to bind and activate the WT LHCGR. Finally, we applied the method to determine the interactions between clinically relevant mutations in the hormone as well as the receptor and show that this assay is fast and effective, plus safer and cost efficient alternative to radioligand-based assays, to screen for mutations in either the receptor or ligand. It enables kinetic measurements in living cells, detection of biosynthesis of the receptor (membrane expression) and it is compatible with downstream cellular assays - including firefly luciferase-based readouts.

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Section: Discussionmentioning

confidence: 99%

Glycoprotein-glycoprotein receptor binding detection using bioluminescence resonance energy transfer (BRET)

Adamczuk

Rivero-Müller

2023

Preprint

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“…Las mutaciones en este receptor explican el 16% del total de los casos de HH idiopático (18). El GNRHR se expresa en las células gonadotropas de la hipófisis y pertenece a la familia de receptores acoplados a proteínas G del tipo A (19,20). Se han descrito cerca de 8 mutaciones diferentes que pueden afectar a este receptor.…”

Section: Mutación Del Receptor De Gnrhunclassified

“…Hay diversas mutaciones activantes e inactivantes del receptor GNRHR, las cuales pueden llevar desde el desarrollo de malignidades hasta los ya mencionados desórdenes reproductivos. También pueden sufrir polimorfismos, sin embargo, su impacto en la acción de la gonadotropina es leve (20).…”

Section: Mutación Del Receptor De Gnrhunclassified

Causas poco frecuentes de amenorrea debida a hipogonadismo hipogonadotrópico

Fernández¹,

Miranda

Sigarán

2023

Rev.méd.sinerg.

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El hipogonadismo hipogonadotrópico es un síndrome clínico de diversas etiologías congénitas o adquiridas, las cuales pueden o no causar amenorrea, ya sea primaria o secundaria, entre otros trastornos de la pubertad. La clasificación del hipogonadismo hipogonadotrópico abarca múltiples patologías que tienen en común una anormalidad en el eje hipotálamo-hipofisario que lleva a una poca o nula estimulación ovárica. Entre las causas congénitas poco comunes se encuentran el síndrome de Kallman, las causas idiopáticas de las cuales se han ido reconociendo mutaciones puntuales como la del CHD7, las mutaciones en la subunidad beta de la hormona foliculoestimulante y la hormona luteinizante; y del receptor de la hormona liberadora de gonadotropina. Respecto a las causas adquiridas poco comunes de amenorrea por hipogonadismo hipogonadotrópico se encuentran la seudociesis, la hipofisitis linfocítica periparto, la enfermedad hepática crónica no alcohólica y la enfermedad renal crónica.

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“…Luteinizing hormone/choriogonadotropin receptor (LHCGR) is involved in the development and maturation of male sexual organs both prenatally and postnatally [ 25 ]. Sexual differentiation is a critical and complex process which normally drives the development towards a consistent pathway with the chromosomal sex of the embryo.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotypic spectrum of LHCGR signal peptide insertion variant: novel clinical and allelic findings causing Leydig cell hypoplasia type II

Hassan,

Mazen,

Elaidy

et al. 2024

Hormones

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Purpose Leydig cell hypoplasia (LCH) type II is a rare disease with only a few cases reported. Patients presented with hypospadias, micropenis, undescended testes, or infertility. In this study, we report a new patient with compound heterozygous variants in the LHCGR gene and LCH type II phenotype. Methods: Whole exome sequencing (WES) was performed followed by Sanger sequencing to confirm the detected variants in the patient and his parents. Results: A novel missense variant (p.Phe444Cys) was identified in a highly conserved site and is verified to be in trans with the signal peptide’s 33-bases insertion variant. Conclusion: Our research provides a more comprehensive clinical and genetic spectrum of Leydig cell hypoplasia type II. It highlighted the importance of WES in the diagnosis of this uncommon genetic disorder as well as the expansion of the genotype of LCH type II.

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Genetic variants of gonadotrophins and their receptors: Impact on the diagnosis and management of the infertile patient

Cited by 14 publications

References 118 publications

Glycoprotein-glycoprotein receptor binding detection using bioluminescence resonance energy transfer (BRET)

Glycoprotein-glycoprotein receptor binding detection using bioluminescence resonance energy transfer (BRET)

Causas poco frecuentes de amenorrea debida a hipogonadismo hipogonadotrópico

Expanding the phenotypic spectrum of LHCGR signal peptide insertion variant: novel clinical and allelic findings causing Leydig cell hypoplasia type II

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