Normosmic idiopathic hypogonadotrophic hypogonadism due to a rare KISS1R gene mutation

Chelaghma, Naziha; Oyibo, Samson O; Rajkanna, Jeyanthy

doi:10.1530/edm-18-0028

Cited by 8 publications

(13 citation statements)

References 13 publications

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“…Males can be clinically manifested as absent or incomplete puberty, small penis, cryptorchidism, and infertility. 12 In the past few years, IHH has classically been categorized as a single-gene disease, 13 but the phenotypic presentation of this disease and its genetic background are highly heterogeneous. 14 A few genes that are involved in the pathogenesis of IHH have been identified at various sites, including TAC3, TACR3, GnRHR, FGFR1, GNRH1, FGF8, KISS1, and KISS1R.…”

Section: Discussionmentioning

confidence: 99%

“…16 Mutations of this gene have been identified in less than 5% of patients with normosmic IHH. 12 Up to now, at least 20 different mutations have been described in the literature, most of which were loss-of-function mutations and were found to have variable clinical manifestation. 12 20 These studies indicated that heterozygous mutations in KISS1R could be also involved in the pathogenesis of IHH.…”

Section: Discussionmentioning

confidence: 99%

“…Idiopathic hypogonadotropic hypogonadism (IHH), which result in azoospermia at the pre‐testicular level, is characterized by a defect in the onset or maintenance of puberty caused by hypothalamic‐pituitary‐gonadal axis dysfunction with the absence of an organic lesion, and its clinical manifestation depends on the onset time. Males can be clinically manifested as absent or incomplete puberty, small penis, cryptorchidism, and infertility . In the past few years, IHH has classically been categorized as a single‐gene disease, but the phenotypic presentation of this disease and its genetic background are highly heterogeneous .…”

Section: Discussionmentioning

confidence: 99%

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Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Geng

Zhang

Liu

et al. 2019

Clinical Laboratory Analysis

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Background: Non-obstructive azoospermia (NOA), a serious phenotype of male spermatogenesis failure, is a multifactorial disease which is regulated by genetic, epigenetic, and environmental factors. Some gene structural variants have been demonstrated to be related to NOA. Loss-of-function mutations of KISS1R cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) which result in azoospermia at the pre-testicular level. The objective of this research was to investigate genetic variants of KISS1R in NOA patients. Methods:The entire coding region of 52 spermatogenesis-associated genes (KISS1R included) was sequenced from 200 NOA patients. Mutation screening was performed to identify genetic variations of these genes by targeted exome sequencing. Sequencing data analysis was carried out by a series of bioinformatics tools.Candidate variants confirmation was performed by Sanger sequencing. Functional analysis of candidate variants was evaluated using SIFT and PolyPhen-2.Results: Three heterozygous missense variants in KISS1R were identified in three patients, respectively. No deleterious variations in other candidate genes were found in the three patients. Two of these three variants, p.A211T and p.G186E, had been reported in the ExAC and dbSNP database, respectively, while the other variant p.A301D was novel. These variants were all predicted to be likely pathogenic by in silico analysis. Conclusion:Our study revealed three heterozygous missense variants in KISS1R which expanded the mutation spectrum of KISS1R in infertile men with NOA in the northeast of China.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Geng

Zhang

Liu

et al. 2019

Clinical Laboratory Analysis

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“…Idiopathic hypogonadotropic hypogonadism with normal sense of smell (normosmic IHH) or with hypoosmia or anosmia (Kallman syndrome) is a complex and rare disorder characterised by insufficient GNRH neuronal action on an otherwise normal hypothalamo-pituitarygonadal axis. This could be due to defective development or migration of GNRH neurones, impaired secretion of GNRH from neurons, disrupted interaction between the GNRH ligand and its receptor, or impaired secretion of LH and FSH (2,3). To date, pathogenic variants in around 50 genes have been reported to cause IHH which account for up to 50% of IHH cases, suggesting that further genes remain to be discovered (4).…”

Section: Introductionmentioning

confidence: 99%

Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings

Sagi

Joshi

Whiles

et al. 2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary Hypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea. Learning points: IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both. Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH. IHH is associated with a wide spectrum of clinical manifestations. IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.

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“…Kiss1-GPR54 signaling is fundamental to GnRH-driven fertility (Leon et al, 2016). Mutation in Kp or in GPR54 are the main reasons for various types of reproductive axis disabilities such as, iodiopathic hypogonadotropic hypogonadism (Kotani et al, 2014), central precocious puberty (Oh et al, 2017) and Normosmic idiopathic hypogonadotrophic hypogonadism (Chelaghma et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Immunocytochemical Detection of Kisspeptin Receptor and Its Association with Motility of Buffalo Bull (Bubalus bubalis) Spermatozoa

Hussain¹

2020

PVJ

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Kisspeptin is a powerful regulator of the hypothalamic-pituitary-gonadal axis. It acts through its receptor GPR54 to regulate sexual maturation, oogenesis, spermatogenesis and fertilization. The present research was implemented to evaluate the presence of kisspeptin receptor on various regions of buffalo bull spermatozoa and to decipher its relationship with different motility parameters of the fresh spermatozoa. Standard swim-up protocol was performed on fresh ejaculates from Nili-Ravi buffalo bulls to obtain three hypothetical layers, having spermatozoa with enhanced motility and normal morphology. The progressive sperm motility was measured in each layer by using phase contrast microscopy. Methanol fixed sperm smears from each layer were processed for standard immunocytochemistry procedure for the detection of kisspeptin receptor using specific antibodies. Maximum GPR54 immunoreactivity was observed in the upper regions (head, neck/midpiece) and moderate immunoreactivity was seen in the lower region (tail) of the spermatozoa in all the three layers. No significant difference in total GPR54 expression was observed in the spermatozoa from three layers and no relationship was observed between percentage motility and GPR54 like ir. Present findings suggest that the buffalo sperm motility is not influenced by GPR54 expression on different regions of the sperm. However, robust GPR54 expression in dorsal areas of buffalo sperm, would raise possibility of a covert function of kisspeptin in the bubaline sperm biology.

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Normosmic idiopathic hypogonadotrophic hypogonadism due to a rare KISS1R gene mutation

Cited by 8 publications

References 13 publications

Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings

Immunocytochemical Detection of Kisspeptin Receptor and Its Association with Motility of Buffalo Bull (Bubalus bubalis) Spermatozoa

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