Prevalence of<i>KISS1 Receptor</i>mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study

Francou, Bruno; Paul, C.; Amazit, Larbi; Cartes, A.; Bouvattier, Claire; Albarel, F.; Maiter, Dominique; Chanson, Philippe; Trabado, Séverine; Brailly-Tabard, Sylvie; Brue, Thierry; Guiochon‐Mantel, Anne; Young, Jacques; Bouligand, Jérôme

doi:10.1093/humrep/dew073

Cited by 51 publications

(35 citation statements)

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“…The GnRH‐R is a member of the GPCR family, which consists of seven‐transmembrane domains (TMDs) connected to each other with extra/intracellular loops (ECL/ICL), but notably it lacks a large intracellular cytoplasmic tail (Millar et al ., ). Homozygous and compound heterozygous mutations in the GNRHR gene are the most frequent genetic causes of ncHH (Francou et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

et al. 2018

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a First co-authors. b Last co-authors.ABSTRACT Background: Normosmic congenital hypogonadotropic hypogonadism (ncHH) is caused by the deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Its typical clinical manifestation is delayed puberty and azoospermia. Homozygous and compound heterozygous mutations in the GNRHR gene (4q13.2) are the most frequent genetic causes of ncHH. Objectives: (i) Characterization at the molecular level (genetic origin and functional effect) of a unique homozygous mutation (p.Gly99Glu) in a ncHH man; (ii) to provide a comprehensive catalog of GNRHR mutations with genotype-phenotype correlation and comparison of in vitro studies vs. in silico prediction tools. Material and Methods: A ncHH man and his parents, in whom we performed the following: (i) Sanger sequencing, qPCR of the GNRHR gene; (ii) chromosome 4 SNP array; and (iii) competition binding assay and inositol phosphate signaling assay. PubMed and Human Genome Mutation Database (HGMD) search for GNRHR mutations. Bioinformatic analysis of 55 reported variants. Results: qPCR showed two GNRHR copies in the index case. SNP array revealed the inheritance of two homologous chromosomes 4 from the mother (maternal heterodisomy; hUPD) with two loss of heterozygosity regions, one of them containing the mutated gene (maternal isodisomy; iUPD). Functional studies for the p.Gly99Glu mutation demonstrated a right-shifted GnRH-stimulated signaling response. Bioinformatic tools show that commonly used in silico tools are poor predictors of the function of ncHH-associated GNRHR variants. Discussion: Functional analysis of the p.Gly99Glu mutation is consistent with severely decreased GnRH binding affinity (a severe partial loss-of-function mutation). Complete LOF variants are associated with severe and severe/moderate phenotype, whereas partial LOF variants show wide range of clinical manifestations. Conclusion: This is the first ncHH patient carrying a novel causative missense mutation of GNRHR with proven 'severe pLOF' due to maternal hUPD/iUPD of chromosome 4. Our literature review shows that functional studies remain essential both for diagnostic and potential therapeutic purposes.

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Section: Introductionmentioning

confidence: 97%

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

et al. 2018

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“…N4 mice siblings were crossed until the N7 generation. Finally, the VO timing of all 13 female mice of the N7 progenies was recorded. All modified ISCSs were verified by genotyping genetic markers on chromosome X.…”

Section: Fine Mappingmentioning

confidence: 99%

“…These observations suggested a crucial role of GPR54 and its ligand Kiss1 in the regulation of puberty. Genome-wide association studies (GWAS) identified sequence variants in or around Lin28B that were associated with age at menarche and other specific characteristics of puberty onset [13][14][15] . An imprinted gene, MKRN3, was found to be related to central precocious puberty by whole-exome sequencing of pedigree samples 16 .…”

Section: Introductionmentioning

confidence: 99%

MiR-505-3p, a New Repressor of Puberty Onset in Female Mice

Li¹,

Wang²,

Zhou³

et al. 2018

Preprint

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Puberty onset is a complex trait regulated by multiple genetic and environmental factors. In this study, we narrowed a puberty-related QTL on chromosome X in female mice to a 1.7 Mb region and deduced that miR-505-3p was the functional gene.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/271718 doi: bioRxiv preprint first posted online Mar. 13, 2018; 2 In a GT1-7 cell line with stable overexpression of miR-505-3p (pGT1-7), both ribosomes and ribosome biogenesis pathways were affected, and the expression of some puberty-related genes was down-regulated. The amount of mRNA and protein products of the Srsf1 gene decreased by 50 percent, and the expression of puberty-related genes was rescued by the overexpression of Srsf1. With the down regulation of Srsf1 expression through shRNA, the mRNA accumulation of puberty-related genes decreased simultaneously in the GT1-7 cell line. The results of RIP-seq showed that SF2, the protein of the Srsf1 gene, primarily bound ribosome protein (RP) mRNAs in GT1-7 cells.miR-505-3p knockout female mice showed earlier vaginal opening, higher serum gonadotrophin levels and higher expression of puberty-related and Srsf1 genes in the hypothalamus than their wild-type littermates. B6 female mice with ectopic expression of miR-505-3p in the hypothalamus showed significant growth retardance and later VO than wild types.These results suggest that miR-505-3p may regulate puberty onset via the Srsf1 gene and RP expression, which reveals a new regulatory pathway in mammalian puberty onset involving microRNA, SF2 and ribosome proteins.Key words: puberty onset, positional cloning, miR-505-3p, GT1-7, CRISPR/Cas9 Author summaryIn this study, we identified miR-505-3p in a puberty-related QTL on the X chromosome as a female puberty onset repressor using a positional cloning strategy. GT1-7 cell lines stably overexpressing miR-505-3p (pGT1-7) showed Kiss1 and GnRH down-regulation. We also identified Srsf1 as the functional target gene of miR-505-3p in GT1-7 cells. Compared to wild-type mice, miR-505-3p knockout female mice showed puberty onset four days sooner, along with the overexpression of miR-505-3p in the hypothalamus 2 days later. Thus, miR-505-3p is a new repressor of puberty onset in female mice.

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“…Congenital hypogonadotropic hypogonadism (CHH) is characterized by deficient or absent pubertal development caused by hyposecretion of gonadotropin. The prevalence of CHH is approximately one case in 8000 individuals [ 1 ]. CHH is divided primarily in two clinical categories: CHH with anosmia or hyposmia (Kallmann syndrome) and CHH with normal smell (normosmic CHH).…”

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confidence: 99%

“…Normosmic CHH has diverse genetic causes, including mutations of KISS1/KISS1R , TAC3/TACR3 , GNRH1/GNRHR , LEP/LEPR , HESX1 , FSHB , and LHB [ 2 ]. KISS1R mutations are found in 2% of patients with normosmic CHH [ 1 ].…”

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confidence: 99%

Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency

Shimizu

Yonekawa

Yoshida

et al. 2017

Journal of the Endocrine Society

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Context:Kisspeptin receptor (KISS1R) is expressed in hypothalamic gonadotropin-releasing hormone neurons and responsible for pubertal onset and reproductive functions. KISS1R mutations remain a rare cause of congenital hypogonadotropic hypogonadism (CHH).Objective:The aim of this study was to identify the genetic cause of CHH in a patient and to functionally characterize a KISS1R mutation.Design:The patient was a 47-year-old Japanese man whose parents were first cousins. He lacked secondary sexual characteristics owing to normosmic CHH. Exon segments for the KISS1R gene in this patient were screened for mutations. Functional analyses were performed using HEK293 cells expressing KISS1R mutants. Molecular dynamics simulations were performed to compare the ligand-KISS1R mutant complex with those of wild-type KISS1R variants.Results:A homozygous mutation (c.440C>T, p.P147L) in KISS1R was identified. The P147L mutation did not affect either receptor expression level or subcellular localization in the recombinant expression system. Intracellular calcium measurements and cellular dielectric spectroscopy demonstrated that the P147L mutation impaired receptor function to an extent more severe than that of a previously reported L148S mutation. A receptor-ligand binding assay showed the P147L mutation causes a substantial loss of ligand-binding affinity. Molecular dynamics simulations revealed the P147L mutation decreases the contact surface area of the ligand-receptor complex in an expanded ligand-binding pocket.Conclusion:We identified a loss-of-function mutation in KISS1R associated with CHH. Our results demonstrated that the P147L mutation causes a severe phenotype and functional impairment resulting from the loss of ligand-binding affinity due to an expanded ligand-binding pocket.

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Prevalence ofKISS1 Receptormutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study

Cited by 51 publications

References 46 publications

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

MiR-505-3p, a New Repressor of Puberty Onset in Female Mice

Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency

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