Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism

Moalla, M.; Kacem, F. Hadj; Al-Mutery, A.F.; Mahfood, Mona; Mejdoub-Rekik, Nabila; Abid, M.; Mnif-Feki, Mouna; Kacem, Hassen Hadj

doi:10.1007/s10815-019-01468-z

Cited by 10 publications

(6 citation statements)

References 25 publications

(69 reference statements)

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“…En parallèle un phénotype identique a été rapporté chez des souris présentant une délétion homozygote du gène GPR-54 (Seminara et al 2003) (Lapatto et al 2007)( Figure 10). Depuis, d'autres mutations de GPR-54 ont été décrites chez l'humain (Brioude et al 2013) (Francou et al 2016) (Nalbantoglu et al 2019) (Moalla et al 2019). De manière générale, les mutations sur le gène de GPR-54 seraient responsables de 2% des HHI (Francou et al 2016).…”

Section: Les Neurones à Kisspeptine a Généralitésunclassified

Impact of Circadian Disruption on Female Mice Reproductive Function

et al. 2020

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In female mammals, cycles in reproductive function depend both on the biological clock synchronized to the light/dark cycle and on a balance between the negative and positive feedbacks of estradiol, whose concentration varies during oocyte maturation. In women, studies report that chronodisruptive environments such as shiftwork may impair fertility and gestational success. The objective of this study was to explore the effects of shifted light/dark cycles on both the robustness of the estrous cycles and the timing of the preovulatory luteinizing hormone (LH) surge in female mice. When mice were exposed to a single 10-hour phase advance or 10-hour phase delay, the occurrence and timing of the LH surge and estrous cyclicity were recovered at the third estrous cycle. By contrast, when mice were exposed to chronic shifts (successive rotations of 10-hoursour phase advances for 3 days followed by 10-hour phase delays for 4 days), they exhibited a severely impaired reproductive activity. Most mice had no preovulatory LH surge at the beginning of the chronic shifts. Furthermore, the gestational success of mice exposed to chronic shifts was reduced, because the number of pups was 2 times lower in shifted than in control mice. In conclusion, this study reports that exposure of female mice to a single phase shift has minor reproductive effects, whereas exposure to chronically disrupted light/dark cycles markedly impairs the occurrence of the preovulatory LH surge, leading to reduced fertility.

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Section: Les Neurones à Kisspeptine a Généralitésunclassified

Impact of Circadian Disruption on Female Mice Reproductive Function

et al. 2020

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“…If the stop codon is altered to code for an amino acid ‘VariO:0309 termination codon change’ occurs. r.1195u>c transition in KISS1R for KISS1 receptor 1 modifies stop codon and causes normosmic congenital hypogonadotropic hypogonadism [ 68 ].…”

Section: Rna Variation Typementioning

confidence: 99%

Systematics for types and effects of RNA variations

Vihinen

2020

RNA Biology

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Systematics is described for annotation of variations in RNA molecules. The conceptual framework is part of Variation Ontology (VariO) and facilitates depiction of types of variations, their functional and structural effects and other consequences in any RNA molecule in any organism. There are more than 150 RNA related VariO terms in seven levels, which can be further combined to generate even more complicated and detailed annotations. The terms are described together with examples, usually for variations and effects in human and in diseases. RNA variation type has two subcategories: variation classification and origin with subterms. Altogether six terms are available for function description. Several terms are available for affected RNA properties. The ontology contains also terms for structural description for affected RNA type, post-transcriptional RNA modifications, secondary and tertiary structure effects and RNA sugar variations. Together with the DNA and protein concepts and annotations, RNA terms allow comprehensive description of variations of genetic and non-genetic origin at all possible levels. The VariO annotations are readable both for humans and computer programs for advanced data integration and mining.

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“…Since then, several other genes have been identified. Indeed, various and numerous proteins are involved in the delicate and complex mechanism of GnRH neuron function, such as kisspeptin (KISS1) and its receptor ( KISS1R ), whose variants cause isolated cHH [ 10 , 11 ], or chromodomain DNA-binding helicase protein ( CHD7 ), whose variants lead to cHH with or without CHARGE syndrome [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series

Cannarella

Gusmano

Condorelli

et al. 2023

IJMS

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Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5–15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype–phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.

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Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism

Cited by 10 publications

References 25 publications

Impact of Circadian Disruption on Female Mice Reproductive Function

Impact of Circadian Disruption on Female Mice Reproductive Function

Systematics for types and effects of RNA variations

Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series

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