kiss1-protein--human and Puberty--Precocious

Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.

Topics: Female; Humans; Kisspeptins; Male; Puberty; Puberty, Precocious

Precocious puberty, as a common pediatric endocrine disease, can be divided into central precocious puberty and peripheral precocious puberty, even though most cases of precocious puberty are diagnosed as central precocious puberty. According to its etiology, central precocious puberty can be further divided into organic and idiopathic central precocious puberty. However, the mechanisms of idiopathic central precocious puberty have not yet been fully elucidated. Currently, four genes, including the kisspeptin gene, the kisspeptin receptor gene, the makorin ring finger protein 3, and the delta-like noncanonical Notch ligand 1, have been implicated in central precocious puberty cases, of which delta-like noncanonical Notch ligand 1 has been determined to represent a key, recently found central precocious puberty-related gene. In this review, we will not only highlight the latest discoveries on the relationship between the delta-like noncanonical Notch ligand 1 system and central precocious puberty but also explore the involvement of the system as well as the Notch signaling pathway in central precocious puberty occurrence.

Topics: Child; Humans; Kisspeptins; Ligands; Puberty, Precocious; Signal Transduction; Ubiquitin-Protein Ligases

Puberty is a crucial biological process normally occurring at a specific time during the lifespan, during which sexual and somatic maturation are completed, and reproductive capacity is reached. Pubertal timing is not only determined by genetics, but also by endogenous and environmental cues, including nutritional and metabolic signals. During the last decade, we have learned much regarding the essential roles of kisspeptins and the neuropeptide pathways that converge on these neurones to modulate kisspeptin signalling, as well as neurokinin B and dynorphin, the co-transmitters of Kiss1 neurones in the arcuate nucleus, and the effects of melanocortins on puberty. Indeed, melanocortins are involved in transmitting the regulatory actions of metabolic cues on pubertal maturation. Intracellular metabolic sensors, such as the AMP-activated protein kinase and the fuel-sensing deacetylase SIRT1, have been shown to contribute to puberty. Further understanding of these signals and regulatory circuits will help uncover the intimacies of the central control of puberty, as well as how alterations in metabolic status, ranging from undernutrition to obesity, affect the pubertal process. Precocious puberty is rare and has a clear female predominance. Central precocious puberty (CPP) is diagnosed when premature activation of the hypothalamic-pituitary axis occurs. Its causes are heterogeneous, with alterations of the central nervous system being of special interest, and with environmental factors also playing a role in some cases. During the last decade, several mutations in different genes (including KISS1, KISS1R, MKRN3 and DLK1) that cause CPP have been discovered. Loss-of-function mutations in MKRN3 are the most common monogenic cause of CPP known to date. Here, we review and update what is known regarding the genotype-phenotype relationship in patients with CPP.

Topics: Female; Humans; Kisspeptins; Male; Melanocortins; Puberty, Precocious; Receptors, Kisspeptin-1; Sexual Maturation; Ubiquitin-Protein Ligases

Kisspeptin is a 54- amino acid peptide that acts as a ligand of a receptor called GPR54 which is basically a transmembrane receptor that spins seven times across the cell membrane and coupled with G-protein. Kisspeptin regulates the development of reproductive functions and the onset of puberty in human and other mammals by acting at the brain, hypothalamus, pituitary and gonad levels of reproductive axis. Kisspeptin is also involved in regulation of trophoblastic invasion during pregnancy, ovulation, and sperm hyperactivation. Inactivating mutations in human kisspeptin gene (KISS1) cause idiopathic hypogonadotropic hypogonadism. Some mutations in human kisspeptin receptor gene (KISS1R) make the receptor inactive which result in idiopathic hypogonadotropic hypogonadism. Some mutations in human KISS1R gene make the receptor prematurely activated and result in the development of central precocious puberty. Central precocious puberty is also caused by some mutations in human KISS1 gene that make the kisspeptin resistant to degradation. This leads to an increased basal kisspeptin level and subsequently the development of central precocious puberty. Higher kisspeptin level has been detected in the serum and plasma of central precocious puberty patients, which suggest that serum or plasma kisspeptin level can be used as a marker for diagnosis of central precocious puberty.

Topics: Animals; Female; Humans; Hypogonadism; Kisspeptins; Pregnancy; Puberty; Puberty, Precocious; Receptors, Kisspeptin-1; Reproduction

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

Topics: Adolescent; Child; Female; Genome-Wide Association Study; Genomic Imprinting; Humans; Kisspeptins; Male; Mutation; Puberty; Puberty, Precocious; Receptors, Kisspeptin-1

Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty to establish reproductive function and regulate the hypothalamic-pituitary-gonadal axis. Premature activation of GnRH secretion leads to idiopathic/central gonadotropin-dependent precocious puberty (CPP). We aimed to compare the blood KP concentrations in girls with CPP and healthy controls.. A systematic review and meta-analysis was performed. We searched MEDLINE, EMBASE, The Cochrane Library, and SciELO. Random-effects model and standardized mean difference (SMD) were used. Heterogeneity was assessed through I2. Meta-regression considered patient age, KP fraction, and analytical method for KP measurement.. The 11 studies included comprised 316 CPP patients and 251 controls. Higher KP levels in the CPP group were found (SMD 1.53; CI 95% = 0.56-2.51). Subgroup analysis revealed association with patient age (p = 0.048), indicating a positive correlation between elevation in KP concentration and age in CPP group. A group of patients with precocious thelarche (PT) from 5 of the included studies comprising 121 patients showed higher levels of KP (1.10; -0.25-2.45: CI 95%) and high heterogeneity (I2 = 91%). The CPP/PT ratio for KP level indicates KP 36% higher on CPP than PT patients.. A consistent difference in KP levels between girls with CPP and controls was identified. While there are important limitations in KP assays which argue against its use as a diagnostic tool, the KP levels in CPP versus control and PT children are consistent with the predicted mechanisms and pathophysiology of CPP.

Topics: Case-Control Studies; Child; Female; Humans; Kisspeptins; Puberty, Precocious

Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44.

Topics: Calcium-Binding Proteins; Gene Silencing; Humans; Intercellular Signaling Peptides and Proteins; Kisspeptins; Membrane Proteins; Methylation; Mutation; Phenotype; Puberty, Precocious; Receptors, Kisspeptin-1; Ribonucleoproteins; Ubiquitin-Protein Ligases

It is widely acknowledged that kisspeptin and its receptor Kiss1R play central regulatory roles in the hypothalamus-pituitary-gonad (HPG) axis and reproduction. Mutations of KISS1 and KISS1R lead to disorders associated with pubertal development, such as central precocious puberty (CPP) and idiopathic hypogonadotropic hypogonadism (IHH). This review focuses on KISS1 and KISS1R mutations found in CPP and IHH and its purposes are twofold: Firstly, based on the mutations found in KISS1 and KISS1R, this review provides insights into the precise mechanism of kisspeptin and the kisspeptin/Kiss1R pathway in the reproductive axis and in puberty. Secondly, G protein-coupled receptors (GPCRs) are known to share highly conserved structural motifs; therefore, knowledge of mutations found at different structural domains of Kiss1R in the diseased state, and how they affect Kiss1R function can be used to decipher GPCR domain function.

Topics: Clinical Studies as Topic; Humans; Hypothalamo-Hypophyseal System; Kisspeptins; Mutation; Puberty, Precocious; Receptors, Kisspeptin-1

Central precocious puberty (CPP) results from early activation of the hypothalamic - pituitary -gonadal (HPG) axis and follows the same sequence as normal puberty. While many factors involved in pubertal initiation remain poorly understood, the kisspeptin system is known to play a key role. Currently, mutations in the kisspeptin system, MKRN3, and DLK1 have been identified in sporadic and familial cases of CPP. The diagnosis is based on physical exam findings indicating advancing puberty and on laboratory tests confirming central HPG axis activation. GnRH analogs are the mainstay of treatment and are used with the goal of height preservation. Newer extended release formulations continue to be developed. Currently there is no evidence of long-term complications associated with treatment. However, many areas remain to be explored such as targeted therapies and aspects of clinical management. Further investigation into psychological effects and additional data regarding long-term outcomes, particularly in males, is needed.

Topics: Calcium-Binding Proteins; Child; Female; Gonadotropin-Releasing Hormone; Humans; Intercellular Signaling Peptides and Proteins; Kisspeptins; Male; Membrane Proteins; Mutation; Puberty, Precocious; Ribonucleoproteins; Ubiquitin-Protein Ligases

A pivotal event in the onset of puberty in humans is the reemergence of the pulsatile release of the gonadotropin-releasing hormone (GnRH) from hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of kisspeptin and its cognate receptor (KISS1/KISS1R) and the inactivation of MKRN3 in the premature reactivation of GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located on the long arm of chromosome 15, encodes makorin ring finger protein 3, which is involved in ubiquitination and cell signaling. The MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explored the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing.

Topics: Animals; Humans; Kisspeptins; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Ribonucleoproteins; Ubiquitin-Protein Ligases

Precocious puberty is a common problem affecting up to 29 per 100,000 girls per year. The earliest identified neuroendocrine change in early puberty thus far is increased kisspeptin secretion from the arcuate nucleus and the anteroventral paraventricular nucleus of the hypothalamus. The regulation of kisspeptin secretion is not well understood, but neurokinin B and dynorphin provide autocrine regulation. The etiologies of precocious puberty may be subdivided into GnRH-dependent and GnRH-independent causes. GnRH-dependent precocious puberty, often called central precocious puberty (CPP), is usually treated with GnRH analogs. Newer developments in the treatment of CPP include expanded data on the safety and efficacy of the subdermal histrelin implant, which is useful for long-term treatment, although removal may be difficult in some cases. Preliminary data suggest that the implant may be left in place for up to 2 years without loss of biochemical suppression. In the last 2 years, more data have been published concerning extended-release leuprolide acetate injections that indicate that the 11.25-mg dose may not provide full biochemical suppression but may clinically suppress signs of puberty, including the accelerated growth velocity and advanced skeletal maturation seen in CPP. Treatment options for familial male-limited precocious puberty and McCune-Albright syndrome are expanding as well, although data are preliminary. Long-term outcome studies of CPP indicate overall good menstrual and reproductive function, but the prevalence of polycystic ovary syndrome may be higher than in the general population. Remarkably few studies have evaluated the behavioral and psychological outcomes of precocious puberty, in contrast to early normal maturation. Additional outcome studies of endocrine, metabolic, and psychological effects of CPP are clearly needed.

Topics: Delayed-Action Preparations; Drug Implants; Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Leuprolide; Male; Puberty; Puberty, Precocious; Treatment Outcome

Kisspeptin is now known to be an important regulator of the hypothalamic--pituitary-gonadal axis and is the target of a range of regulators, such as steroid hormone feedback, nutritional and metabolic regulation. Kisspeptin binds to its cognate receptor, KISS1R (also called GPR54), on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion-thus gating down-stream events supporting reproduction. The development of peripherally active kisspeptin antagonists could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer. The following chapter discusses the advances made in the search for both peptide and small molecule kisspeptin antagonists and their use in delineating the role of kisspeptin within the reproductive system. To date, four peptide antagonists and one small molecule antagonist have been designed.

Topics: Animals; Endometriosis; Female; Gonadotropin-Releasing Hormone; Humans; Infertility; Kisspeptins; Male; Neurons; Prostatic Neoplasms; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction

The neuropeptide kisspeptin, encoded by the Kiss1 gene, is required for mammalian puberty and fertility. Examining the development of the kisspeptin system contributes to our understanding of pubertal progression and adult reproduction and sheds light on possible mechanisms underlying the development of reproductive disorders, such as precocious puberty or hypogonadotropic hypogonadism. Recent work, primarily in rodent models, has begun to study the development of kisspeptin neurons and their regulation by sex steroids and other factors at early life stages. In the brain, kisspeptin is predominantly expressed in two areas of the hypothalamus, the anteroventral periventricular nucleus and neighboring periventricular nucleus (pre-optic area in some species) and the arcuate nucleus. Kisspeptin neurons in these two hypothalamic regions are differentially regulated by testosterone and estradiol, both in development and in adulthood, and also display differences in their degree of sexual dimorphism. In this chapter, we discuss what is currently known and not known about the ontogeny, maturation, and sexual differentiation of kisspeptin neurons, as well as their regulation by sex steroids and other factors during development.

Topics: Adult; Animals; Anterior Thalamic Nuclei; Arcuate Nucleus of Hypothalamus; Estradiol; Female; Gene Expression Regulation; Humans; Hypogonadism; Kisspeptins; Male; Puberty; Puberty, Precocious; Reproduction; Sex Characteristics; Testosterone

Sex steroid hormones, most notably estradiol, play a pivotal role in the sex-specific organization and function of the kisspeptin system. Endocrine--disrupting compounds are anthropogenic or naturally occurring compounds that interact with steroid hormone signaling. Thus, these compounds have the potential to disrupt the sexually dimorphic ontogeny and function of kisspeptin signaling pathways, resulting in adverse effects on neuroendocrine physiology. This chapter reviews the small but growing body of evidence for endocrine disruption of the kisspeptin system by the exogenous estrogenic compounds bisphenol A, polychlorinated biphenyl mixtures, and the phytoestrogen genistein. Disruption is region, sex, and compound specific, and associated with shifts in the timing of pubertal onset, irregular estrous cycles, and altered sociosexual behavior. These effects highlight that disruption of kisspeptin signaling pathways could have wide ranging effects across multiple organ systems, and potentially underlies a suite of adverse human health trends including precocious female puberty, idiopathic infertility, and metabolic syndrome.

Topics: Animals; Benzhydryl Compounds; Estradiol; Female; Genistein; Humans; Infertility; Kisspeptins; Menstrual Cycle; Metabolic Syndrome; Neurosecretory Systems; Phenols; Phytoestrogens; Puberty, Precocious; Sexual Behavior; Signal Transduction

Kisspeptin is a 54-amino acid peptide which is encoded by the KiSS-1 gene and activates the G protein-coupled receptor GPR54. Evidence suggests that this system is a key regulator of mammalian and human reproduction. Animal studies have shown that GPR54-deficient mice have abnormal sexual development. Central and peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis whilst pre-administration of a gonadotrophin releasing hormone (GnRH) antagonist abolishes this effect. In humans, inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism whilst activation of GPR54 signalling is associated with premature puberty. In healthy human volunteers, the acute intravenous administration of kisspeptin potently increases plasma luteinising hormone (LH) levels and significantly increases plasma follicle stimulating hormone (FSH) and testosterone without side effects in both males and in females particularly in the preovulatatory phase of the menstrual cycle. In infertility due to hypothalamic amenorrhoea acute administration of kisspeptin results in stimulation of reproductive hormones. The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans. Hence kisspeptin has potential as a novel tool for the manipulation of the HPG axis and treatment of infertility in humans. This review discusses the evidence highlighting kisspeptin's key role in human reproduction.

Topics: Amenorrhea; Amino Acid Sequence; Animals; Female; Humans; Hypogonadism; Infertility; Kisspeptins; Male; Molecular Sequence Data; Mutation; Puberty; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction

Since 2003, kisspeptin and its receptor (KISS1R, also called GPR54) are recognized as major actors of the gonadotrope axis. Mutations of genes encoding the peptide or the receptor have been identified in patients with precocious puberty or hypogonadotropic hypogonadism. They are strong stimulators of GnRH neurons and are involved in various mechanisms regulating gonadotrope axis as puberty induction or positive and negative feedback regulation on the gonadotrope axis by gonadal steroids. They also mediated some metabolic or environmental signals on the reproduction axis. Kisspeptins are synthesized and secreted by hypothalamic nuclei located in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). This system is complex because neurons located in the ARC coexpress many neuromediators such as neurokinin B and dynorphin, involved in the control of gonadotrope axis. During pregnancy, kisspeptins are also secreted by placenta and should be involved in trophoblastic invasion. After kisspeptin administration to male and female animals as well as to women with hypothalamic secondary amenorrhoea, they are able to stimulate GnRH and gonadotrophin secretion. Then, kisspeptin agonists appear as valuable new tools in treatment for reproduction troubles. The aim of this review is to clarify the role of kisspeptins in regulating gonadotrophin secretion and explores their possible therapeutic use.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hypogonadism; Kisspeptins; Male; Mice; Mice, Knockout; Mutation; Neurons; Paraventricular Hypothalamic Nucleus; Placenta; Pregnancy; Puberty; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction

Human puberty is triggered by the reemergence of GnRH pulsatile secretion with progressive activation of the gonadal function. A number of genes have been identified in the complex regulatory neuroendocrine network that controls puberty initiation. KISS1 and KISS1R genes, which encode kisspeptin and its cognate receptor, respectively, are considered crucial factors for acquisition of normal reproductive function. Recently, rare missense mutations and single nucleotide polymorphisms (SNPs) of the kisspeptin system were associated with puberty onset. Two gain-of-function mutations of the KISS1 and KISS1R genes were implicated in the pathogenesis of GnRH-dependent precocious puberty, previously considered idiopathic. These discoveries have yielded significant insights into the physiology and pathophysiology of this important life transition time. Here, we review the current molecular defects that are implicated in human GnRH-dependent precocious puberty.

Topics: Animals; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Mutation; Puberty, Precocious

Kisspeptin has emerged as a critical player in the initiation of puberty and reproductive function. In humans, inactivating mutations of the kisspeptin receptor result in hypogonadotrophic hypogonadism and kisspeptin receptor activating mutations cause precocious puberty. Kisspeptin potently stimulates the release of gonadotrophins predominantly through the release of gonadotrophin-releasing hormone (GnRH). Here we review the data from animal and human studies exploring the role of kisspeptin in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin signalling presents a novel target for therapeutic manipulation of the HPG axis.

Topics: Animals; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Kisspeptins; Puberty; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; Signal Transduction; Tumor Suppressor Proteins

The involvement of kisspeptin and neurokinin in B pathways in the reproductive axis was first suspected by linkage analysis in consanguineous families with isolated hypogonadotropic hypogonadism (IHH). Since then, several loss-of-function mutations affecting the kisspeptin receptor and neurokinin B and its receptor were associated with sporadic and familial IHH without olfactory abnormalities or other associated developmental alterations. Clinical manifestations were indistinguishable in individuals with mutations affecting these pathways. Micropenis and cryptorchidism were common findings among male patients. Response to acute GnRH stimulation varied from blunted to normal, and many affected males and females were successfully treated for infertility with either exogenous gonadotropins or long term pulsatile GnRH infusion. More recently, rare activating mutations of the kisspeptin and its receptor were identified in children with idiopathic central precocious puberty, supporting the crucial role of this system in the human pubertal onset. Kisspeptin is a potent excitatory regulator of the GnRH secretion, whereas the role of neurokinin B in the neuroendocrine control of the reproductive axis is still poorly understood. Interestingly, kisspeptin and neurokinin B are coexpressed in the arcuate nucleus in the mammalian hypothalamus, suggesting that these systems are closely related and potential partners of the regulation of the reproductive axis.

Topics: Amino Acid Sequence; Animals; Female; Gonads; Humans; Kisspeptins; Male; Molecular Sequence Data; Neurokinin B; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; Signal Transduction; Tumor Suppressor Proteins

In 2003, three groups around the world simultaneously discovered that KISS1R (GPR54) is a key gatekeeper of sexual maturation in both mice and men. Developmental changes in the expression of the ligand for KISS1R, kisspeptin, support its critical role in the pubertal transition. In addition, kisspeptin, a powerful stimulus of GNRH-induced gonadotropin secretion and may modulate both positive and negative sex steroid feedback effects at the hypothalamic level. Genetic studies in humans have revealed both loss-of-function and gainof-function mutations in patients with idiopathic hypogonadotropic hypogonadism and precocious puberty respectively. This review examines the kisspeptin/KISS1R pathway in the reproductive system.

Topics: Animals; Female; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Kisspeptins; Luteinizing Hormone; Male; Mice; Mutation; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; Sexual Maturation; Tumor Suppressor Proteins

Puberty is controlled by genetic and environmental factors. This review examines the genetic basis for puberty by evaluating known gene mutations associated with disordered puberty in humans. At present, at least 17 different single-gene mutations are recognized as being associated with delayed or absent puberty in humans. Several of these genes are involved in the development of the olfactory nervous system, with mutations typically resulting in anosmia/hyposmia and hypogonadotropic hypogonadism, otherwise known as Kallmann syndrome. The biological basis for the association between smell and fertility is strong as development of the gonadotropin-releasing hormone (GnRH) neurons, responsible for regulating fertility, is intricately associated with development of the olfactory system. Other gene mutations, including the recently discovered kisspeptin-GPR54 signalling system, affect puberty by directly or indirectly modulating the functioning of the GnRH neurons and pituitary gonadotrophs. Together, these single-gene mutations are presently estimated to account for approximately 30% of individuals with disorders of puberty.. A large number of different genes are involved in the complex process of bringing about reproductive competency. In addition to the genetic mutations associated with precocious and delayed puberty, the oligogenic aetiology of these conditions is being increasingly appreciated.

Topics: Brain; Child Development; Embryonic Development; Humans; Hypogonadism; Infant; Kallmann Syndrome; Kisspeptins; Mutation; Puberty; Puberty, Delayed; Puberty, Precocious; Tumor Suppressor Proteins

There is controversial results about serum kisspeptin, neurokinin-B (NKB), anti-Müllerian hormone (AMH) and inhibin B (INHB) levels in girls with central precocious puberty (CPP). Aim of this study is to evaluate serum levels of these four peptides in patients presented with early pubertal signs, and to evaluate their diagnostic validity in the diagnosis of CPP.. Cross-sectional study.. Study included 99 girls (51 CPP, 48 premature thelarche [PT]) whose breast development started before 8 years and 42 age-matched healthy prepubertal girls. Clinical findings, antropometric measurements, laboratory and radiological findings were recorded. Gonadotropin-releasing hormone (GnRH) stimulation test was performed in all cases with early breast development.. Kisspeptin, NKB, INHB and AMH levels were measured in fasting serum samples using enzyme-linked immunosorbent assay method.. There was no statistically significant difference between mean ages of girls with CPP (7.1 ± 1.2 years), PT (7.2 ± 1.3 years) and prepubertal controls (7.0 ± 1.0 years). Serum kisspeptin, NKB and INHB levels were higher in CPP group compared to PT and control groups, while serum AMH level was lower in CPP group. Serum kisspeptin, NKB, and INHB were all positively correlated with bone age (BA) advancement, and peak luteinizing hormone in GnRH test. Multiple stepwise regression analysis revealed that the most important factors used to differentiate CPP from PT were advanced BA, serum kisspeptin, NKB and INHB levels (AUC: 0.819, p < .001).. We, first showed in the same patients' group that serum kisspeptin, NKB and INHB were higher in patients with CPP and can be used as alternative parameters to distinguish CPP from PT.

Topics: Anti-Mullerian Hormone; Child; Child, Preschool; Cross-Sectional Studies; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Neurokinin B; Puberty; Puberty, Precocious

Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in. Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the. Three previously described pathogenic. The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.

Topics: Brain Diseases; Calcium-Binding Proteins; Child; Child, Preschool; Cohort Studies; Cyprus; DNA Mutational Analysis; Exome Sequencing; Female; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Kisspeptins; Male; Membrane Proteins; Mutation; Puberty, Precocious; Receptors, Kisspeptin-1; Ubiquitin-Protein Ligases

This case control study was designed to investigate the association between mutation of 10 single nucleotide polymorphism (SNP) loci (rs1132506, rs5780218, rs192636495, rs4889, rs184749, rs12985070, rs708910, rs932491, rs8074995, and rs2306877) in all 5 genes (KISS1, GPR54, PLCB1, PRKCA, and ITPR1) in the kisspeptin/GPR54 pathway and the risk of early puberty in Chinese Han girls.. A total of 314 pairs of early puberty girls on their first visit to hospital and age-matched controls (± 3 months) were recruited. The genotypes of each SNP were determined and the effect of loci variation on early puberty was investigated.. rs5780218 was significantly associated with early puberty in additive, dominant, and recessive models of inheritance after adjusting for confounding factors (Pr < .05). After stratification, rs5780218 variation (odds ratio [OR], 1.650, 95% confidence interval [CI], 1.155-2.355 in additive models and OR, 2.116; 95% CI, 1.187-3.770 in recessive models) increased the risk of central precocious puberty (CPP); mutation in rs708910 (OR, 2.768; 95% CI, 1.305-5.872 in recessive model) had a positive association with the risk of CPP; and rs932491 variation was negatively associated with early and fast puberty (EFP) (OR, 0.309; 95% CI, 0.144-0.661 in additive models and OR, 0.317; 95% CI, 0.141-0.713 in dominant models).. Our study suggests that mutation in rs5780218 and rs708910 increases the risk of CPP. rs932491 variation may have a protective effect on the risk of EFP. Further studies in larger populations or with people from different regions are needed to verify our findings.

Topics: Asian People; Biomarkers; Case-Control Studies; Child; Female; Follow-Up Studies; Humans; Kisspeptins; Polymorphism, Single Nucleotide; Prognosis; Puberty, Precocious; Receptors, Kisspeptin-1

The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty in association with the decrease in MKRN3 expression in the medial basal hypothalamus of mice before the initiation of reproductive maturation suggests that MKRN3 is acting as a brake on gonadotropin-releasing hormone (GnRH) secretion during childhood. In the current study, we investigated the mechanism by which MKRN3 prevents premature manifestation of the pubertal process. We showed that, as in mice, MKRN3 expression is high in the hypothalamus of rats and nonhuman primates early in life, decreases as puberty approaches, and is independent of sex steroid hormones. We demonstrated that Mkrn3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and that MKRN3 repressed promoter activity of human KISS1 and TAC3, 2 key stimulators of GnRH secretion. We further showed that MKRN3 has ubiquitinase activity, that this activity is reduced by MKRN3 mutations affecting the RING finger domain, and that these mutations compromised the ability of MKRN3 to repress KISS1 and TAC3 promoter activity. These results indicate that MKRN3 acts to prevent puberty initiation, at least in part, by repressing KISS1 and TAC3 transcription and that this action may involve an MKRN3-directed ubiquitination-mediated mechanism.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Female; Gene Expression Regulation; Gonadotropin-Releasing Hormone; HEK293 Cells; Humans; Kisspeptins; Male; Mice; Neurokinin B; Neurons; Promoter Regions, Genetic; Puberty, Precocious; Rats, Sprague-Dawley; Transcription, Genetic; Ubiquitin-Protein Ligases

BACKGROUND This study was designed to investigate the effect of high-glucose and high-fat condition on estrogen receptor- and sexual precocity-related genes in GT1-7 cells. MATERIAL AND METHODS In this study, CCK8 was used to detect cell viability, and TUNEL assay was used to detect apoptosis levels of GT1-7 cells after treatment with glucosamine and palmitate. The expression level of GnRH was measured by ELISA and RT-qPCR. RT-qPCR and Western blot were used to detect the expression of ERß, CD36, and GPR54 in GT1-7 cells, and the expression of ERß was detected using immunohistochemistry analysis. Finally, after adding the intervening drug tamoxifen to GT1-7 cells, the expression level of GnRH was measured by ELISA and Western blot analysis was used to detect the expression of GPR54 and GnRH. RESULTS GnRH secretion in the high-fat and high-glucose group increased continuously over time and peaked at 18 h, and GnRH gene expression peaked at 12 h. High-fat and high-glucose conditions also significantly increased the levels of estrogen receptors ß (ERß), fatty acid translocase protein (CD36), and G Protein-Coupled Receptors 54 (GPR54) in GT1-7 cells. After estrogen receptors ß (ER) was inhibited, GnRH secretion and GPR54 expression were decreased at 12 h and 18 h. CONCLUSIONS Our study demonstrates that high-glucose and high-fat conditions promote the secretion of GnRH and ER and the expression of genes related to sexual precocity in GT1-7 cells.

Topics: Animals; Apoptosis; CD36 Antigens; Cell Line; Cell Survival; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Gene Expression; Glucosamine; Glucose; Gonadotropin-Releasing Hormone; Kisspeptins; Mice; Palmitates; Puberty, Precocious; Receptors, Estrogen; Receptors, Kisspeptin-1

Childhood obesity, especially in girls, is frequently bound to earlier puberty, which is linked to higher disease burden later in life. The mechanisms underlying this association remain elusive. Here we show that brain ceramides participate in the control of female puberty and contribute to its alteration in early-onset obesity in rats. Postnatal overweight caused earlier puberty and increased hypothalamic ceramide content, while pharmacological activation of ceramide synthesis mimicked the pubertal advancement caused by obesity, specifically in females. Conversely, central blockade of de novo ceramide synthesis delayed puberty and prevented the effects of the puberty-activating signal, kisspeptin. This phenomenon seemingly involves a circuit encompassing the paraventricular nucleus (PVN) and ovarian sympathetic innervation. Early-onset obesity enhanced PVN expression of SPTLC1, a key enzyme for ceramide synthesis, and advanced the maturation of the ovarian noradrenergic system. In turn, obesity-induced pubertal precocity was reversed by virogenetic suppression of SPTLC1 in the PVN. Our data unveil a pathway, linking kisspeptin, PVN ceramides, and sympathetic ovarian innervation, as key for obesity-induced pubertal precocity.

Topics: Animals; Ceramides; Female; Hypothalamus; Kisspeptins; Male; Ovary; Pediatric Obesity; Puberty, Precocious; Rats, Wistar

This study investigated the relationships of circulating leptin, kisspeptin, and neurokinin B (NKB) levels with precocious puberty (PP) in overweight/obese girls and evaluated the usefulness of these markers in the initiation of puberty. One hundred and twenty-eight girls aged 7.0-8.9 years with PP (group A, normal-weight; group B, overweight/obese) and 30 age-matched normal controls (NC) were enrolled. Serum levels of leptin, kisspeptin, and NKB were measured by commercial kits. Serum leptin levels were higher in group A (4.21 ng/mL) and B (5.64 ng/mL) compared to the NC (2.35 ng/mL, p < .001). Serum kisspeptin levels were lower in group A (0.59 ng/mL) than in group B (0.66 ng/mL, p = .018). Serum NKB levels were not different among the three groups. The predictive value of leptin (AUC =0.791) was lower than that of IGF-1 (AUC =0.917, p = .009), although both were significant markers for PP in the regression analysis. BMI z-score (AUC =0.806) was a predictive factor of PP. In conclusion, a higher level of leptin, IGF-1, and fatness in overweight/obese girls with PP compared to the NC confirms their roles in the regulation of puberty. Further research is needed if the effects of kisspeptin and NKB on puberty are limited at the levels of neurons or target tissue.

Topics: Biomarkers; Body Mass Index; Case-Control Studies; Child; Female; Humans; Kisspeptins; Leptin; Neurokinin B; Overweight; Pediatric Obesity; Predictive Value of Tests; Puberty, Precocious; Sexual Maturation

The aim of this study was to determine the serum levels of kisspeptin and ghrelin (GAH), as well as the relationship of these two peptides with each other in premature thelarche (PT) and premature adrenarche (PA) cases and to investigate the possibility of using these peptides as markers in the differentiation of puberty disorders.. A PT group aged 1-8 years (n = 40), a PA group aged 1-9 years (n = 23, female/male = 20/3) and control groups consistent with each of the previous groups in terms of age and gender were created for the study. Kisspeptin and ghrelin levels were measured with ELISA methods from blood samples drawn while fasting in the morning.. When the PT group was compared with the controls, the plasma kisspeptin levels of the cases were significantly higher than the control group (165.47 ± 15.45 pmol/L, 96.82 ± 12.33 pmol/L, p = 0.005, respectively). Kisspeptin levels in the PA group did not show a difference with the control group (121.36 ± 17.99 pmol/L, 95.52 ± 11.54 pmol/L, p = 0.249, respectively). No significant difference could be found when GAH levels in the PT and PA groups were compared with controls. No significant correlation was found between kisspeptin and GAH levels in the PT and PA groups.. Our results indicate that kisspeptin plays an important role in the PT, but GAH is not associated with puberty disorders.

Topics: Adrenarche; Biomarkers; Case-Control Studies; Child; Child, Preschool; Female; Ghrelin; Humans; Infant; Kisspeptins; Male; Puberty, Precocious; Sexual Maturation

Childhood obesity and obesity-related metabolic complications are induced by a high-fat postnatal diet. The lack of a suitable animal model, however, remains a considerable challenge in obesity studies. In the current study, we provided high-fat diet (HFD) to dams during lactation and to pups after weaning. We also developed a novel model of C57BL/6J mouse pups with HFD-induced postnatal obesity. Results showed that feeding with HFD induces fat deposition and obesity in pups. Furthermore, HFD more potently increased the body weight (BW) of male than female pups. HFD-fed female pups were obese, underwent precocious puberty, and showed increased kisspeptin expression in the hypothalamus. However, parental obesity and precocious puberty exerted no synergistic effects on the HFD-induced postnatal weight gain and puberty onset of the pups. Interestingly, some HFD-fed litters with normal BW also exhibited precocious puberty. This finding suggested that diet composition but not BW triggers puberty onset. Our model suggests good construction validity of obesity and precocious puberty. Furthermore, our model can also be used to explore the mutual interactions between diet-induced postnatal childhood obesity and puberty.

Topics: Animals; Animals, Newborn; Diet, High-Fat; Female; Kisspeptins; Lactation; Male; Mice; Mice, Inbred C57BL; Obesity; Puberty, Precocious; Sexual Maturation; Weaning; Weight Gain

The aim of the present study was to compare serum leptin, kisspeptin, total adiponectin, high molecular weight (HMW) adiponectin and neuropeptide Y (NPY) levels between girls with central precocious puberty (CPP; n=26, 7-9.5 years old) and age-matched controls (n=29) including or excluding obese girls. Leptin and NPY levels were comparable between CPP and control girls. Kisspeptin levels were lower in the CPP than control group, and were positively correlated with oestrogen in the control group and with systolic and diastolic blood pressure in the CPP group. Kisspeptin levels were negatively correlated with FSH and LH in the CPP group. Total adiponectin levels were lower in CPP than control girls, and were negatively correlated with Tanner stage and body mass index, but positively correlated with the quantitative insulin sensitivity check index in the control group. HMW adiponectin was higher in the CPP than control group, and was positively correlated with Tanner stage and LH in all girls. Total adiponectin had a strong positive correlation with HMW adiponectin in the CPP group (r=0.915) compared with the control group (r=0.371). In conclusion, kisspeptin may be associated with increased oestrogen in prepubertal girls, but with increased blood pressure in girls with CPP. In girls entering puberty, HMW adiponectin was increased and associated with reproductive parameters. Based on these observations, HMW adiponectin probably plays an essential role in the initiation of puberty and is a candidate marker for the prediction of CPP.

Topics: Adiponectin; Biomarkers; Case-Control Studies; Child; Female; Humans; Kisspeptins; Leptin; Molecular Weight; Neuropeptide Y; Puberty, Precocious

To find out the diagnostic role of kisspeptin and neurokinin B in idiopathic central precocious puberty (ICPP) and premature thelarche (PT).. The girls who presented with early breast development before the age of 8 years were evaluated. Patients with intracranial pathologies were excluded. Basal and stimulated follicle-stimulating hormone/luteinizing hormone (LH) levels and basal neurokinin B/kisspeptin levels were measured. Patients who had peak value of LH >5 mIU/mL and a bone age (BA)/chronological age (CA) ratio >1.1 were diagnosed as central precocious puberty (CPP), while cases who did not meet these criteria were diagnosed as PT. Healthy age-matched prepubertal girls were included as the control group.. The study group contained 25 girls with ICPP (7±0.8 years), 35 girls with PT (6.8±0.7 years), and 30 controls (6.7±0.7 years). Basal serum kisspeptin and neurokinin B levels were 2.36±0.47 ng/mL and 2.61±0.32 ng/mL, respectively in the ICPP group, 2.23±0.43 ng/mL and 2.24±0.23 ng/mL, respectively in the PT group, and 1.92±0.33 ng/mL and 2.03±0.24 ng/mL, respectively in the controls. Both kisspeptin and neurokinin B levels were higher in the ICPP and PT groups compared to controls (p<0.05). Moreover, basal neurokinin B level was different between ICPP and PT groups (p<0.01). A serum neurokinin B level of 2.42 ng/mL provided the most appropriate level to differentiate ICPP from PT, with a sensitivity of 84% and specificity of 77.1%.. Differentiation of CPP from PT is sometime difficult, and there is a need for a simple method for the differential diagnosis. Our results suggest that basal serum neurokinin B level can be used as an adjunctive parameter to differentiate ICCP from PT.

Topics: Breast; Child; Diagnosis, Differential; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Neurokinin B; Puberty, Precocious; ROC Curve

Bisphenol A (BPA) is known as an endocrine disruptor and it is supposed to have a role on the development of central precocious puberty (CPP). Kisspeptin, a hypothalamic peptide, is a neuromodulator of gonadotropin releasing hormone and it has an important role on regulation of the onset of puberty. The BPA levels in girls with CPP and premature thelarche (PT) and its relation with kisspeptin levels were investigated.. Twenty-eight girls with CPP, 28 girls with PT and 22 prepubertal girls as a control group were enrolled to the study. Urinary BPA and serum kisspeptin levels were compared in the groups. Bivariate correlations were performed to evaluate the relations of BPA with kisspeptin and estradiol.. There was no statistical difference between groups regarding BPA levels. Serum kisspeptin levels were higher in CPP group than controls [306.56 (interquartile range (IQR), 175.63-504.66) vs. 157.62 (IQR, 55.61-285.00) p: 0.008]. There were no correlations between BPA and kisspeptin levels (r: 0.088, p: 0.391) and between BPA and estradiol (r: -0.171, p: 0.144).. The BPA levels did not differentiate between groups and it seems that the exposed amount of BPA in daily life did not affect kisspeptin levels in girls with CPP and PT.

Topics: Benzhydryl Compounds; Biomarkers; Case-Control Studies; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Kisspeptins; Male; Phenols; Prognosis; Puberty, Precocious; Sexual Maturation

Low-dose administration of manganese chloride (MnCl2) causes release of hypothalamic LH-releasing hormone (LHRH) and advances puberty in rat. Recently, this element was shown to up-regulate mammalian target of rapamycin (mTOR), kisspeptin gene (KiSS-1), and LHRH gene expressions in the brain preoptic area (POA)/anteroventral periventricular (AVPV) nucleus. Because these genes are critical for puberty, this study was conducted to identify the upstream mechanism by which Mn activates the mTOR/KiSS-1 pathway. On day 12, immature female rats began receiving a daily supplemental dose of 10 mg/kg of MnCl2 or saline by gavage, and POA/AVPV tissues were collected on day 29 for specific protein assessments. Another experiment assessed in vitro IGF-1 release in response to Mn and assessed signal transduction pathways in the POA/AVPV region after Mn delivery into the third ventricle. Chronic Mn exposure increased (P < .05) basal expressions of mTOR and kisspeptin proteins. Mn increased protein kinase B (Akt) and Ras homolog enriched in brain, both capable of activating mTOR. Central Mn delivery increased expressions of phosphorylated IGF-1 receptor (IGF-1R) (P < .05) and Akt (P < .01) in the POA/AVPV region. The previous central delivery of JB1, an IGF-1R antagonist, blocked Mn-induced expressions of both phosphorylated IGF-1R and Akt. Downstream to Akt, centrally administered Mn increased tuberous sclerosis complex 2 (P < .05), Ras homolog enriched in brain (P < .01), mTOR (P < .05), and kisspeptin (P < .05). Finally, we observed that the early puberty induced by Mn was blocked by the administration of an mTOR inhibitor. These results suggest that Mn acts, at least in part, through the IGF-1/Akt/mTOR pathway to influence prepubertal kisspeptin and LHRH.

Topics: Animals; Animals, Newborn; Female; Insulin-Like Growth Factor I; Kisspeptins; Manganese; Oncogene Protein v-akt; Pregnancy; Puberty, Precocious; Rats; Rats, Sprague-Dawley; Sexual Maturation; Signal Transduction; TOR Serine-Threonine Kinases

Sporadic epidemics and several researches in rodents indicated that zearalenone (ZEA) and its metabolites, the prevailing oestrogenic mycotoxins in foodstuffs, were a triggering factor for true precocious puberty development in girls. Nevertheless, the neuroendocrine mechanism through which ZEA mycoestrogens advance puberty onset is not fully understood. To elucidate this issue, hypothalamic kisspeptin-G-protein coupled receptor-54 (GPR54) signaling pathway that regulates the onset of puberty was focused on in the present study. Immature female SD rats were given a daily intragastric administration of corn oil (vehicle control), 50 μg/kg body weight (bw) of 17β-estradiol (E2, positive control), and 3 doses (0.2, 1 and 5 mg/kg bw) of ZEA for consecutive 5 days starting from postnatal day 15, respectively. Puberty onset was evaluated by detecting the physiological and hormonal responses, and hypothalamic kisspeptin-GPR54 pathway was determined to reveal the neuroendocrine mechanism. As the markers of puberty onset, vaginal opening was significantly accelerated and uterine weight was increased in both E2 and 5 mg/kg ZEA groups. Serum levels of follicle stimulating hormone, luteinizing hormone and estradiol were also markedly elevated by E2 and 5 mg/kg ZEA, which is compatible with the changes in peripheral reproductive organs. The mRNA and protein expressions of hypothalamic gonadotropin-releasing hormone (GnRH) were both obviously elevated by E2 and 5 mg/kg ZEA. GnRH expression changes occurred in parallel with increased expressions of hypothalamic Kiss1 and its receptor GPR54 at both mRNA and protein levels. Most of these changes were also noted in 1 mg/kg ZEA group, but none in 0.2 mg/kg group. Therefore, within the context of this study, the No Observed Adverse Effect Level (NOAEL) for ZEA in terms of oestrogenic activity and puberty-promoting effect in immature female rats was considered to be 0.2 mg/kg bw per day, and the Lowest Observed Adverse Effect Level (LOAEL) was 1 mg/kg bw per day. In conclusion, prepubertal exposure to dietary relevant levels of ZEA induced central precocious puberty in female rats by premature activation of hypothalamic kisspeptin-GPR54-GnRH signaling pathway, followed by the stimulation of gonadotropins release at an earlier age, resulting in the advancement of vaginal opening and enlargement of uterus at periphery.

Topics: Animals; Estrogens; Estrous Cycle; Female; Genitalia, Female; Gonadotropin-Releasing Hormone; Hormones; Hypothalamus; Kisspeptins; Male; Mycotoxins; Pituitary Gland; Puberty, Precocious; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, LHRH; RNA, Messenger; Sexual Maturation; Signal Transduction; Zearalenone

The aim of the present study was to investigate the diagnostic role of serum neurokinin B level and its relationship with kisspeptin and leptin, which are known to be involved in the initiation of pubertal process. Girls who presented with breast development (<8 years) were included in the study. All patients underwent bone age assessment. Basal levels of serum follicle stimulating hormone and luteinizing hormone were measured and gonadotropin releasing hormone stimulation test was performed. Patients with a bone age/chronological age ratio >1 and a peak luteinizing hormone response in gonadotropin releasing hormone stimulation test >5mIU/L were included in the central precocious puberty group, while patients who did not meet these criteria were included in the premature thelarche group. Patients with organic pathologies were excluded. Healthy prepubertal girls with similar age were included as the control group. Leptin, kisspeptin and neurokinin B levels were measured by ELISA method. The study included 20 girls with idiopathic central precocious puberty 22 girls with premature thelarche and 24 prepubertal controls. While serum kisspeptin, leptin and neurokinin B levels were significantly higher in central precocious puberty and premature thelarche groups compared to controls, no significant difference was found between central precocious puberty and premature thelarche groups. Increased serum levels of leptin, kisspeptin and neurokinin B in patients with premature thelarche and central precocious puberty suggest that they take part during the initiation of pubertal process, however, these markers are not able to differentiate patients with central precocious puberty from premature thelarche.

Topics: Biomarkers; Child; Child, Preschool; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kisspeptins; Leptin; Neurokinin B; Puberty, Precocious

Kisspeptin is a hypothalamic neuropeptide playing a physiological role in human reproduction. Genetic over-activation of kisspeptin causes precocious puberty in children. Concentrations of circulating kisspeptin are low in adults. The concentrations of plasma kisspeptin in boys and girls have not been studied previously.. Blood was obtained from 51 children and 63 adults. Plasma samples were analysed using radioimmunoassay. Children were aged 2-18 years, and attending hospital for a medically requested blood test unrelated to reproductive development. Data on pubertal status were not collected due to ethical reasons.. Mean plasma kisspeptin was significantly higher in children when compared with adults (mean plasma kisspeptin in pmol/L: 12.3 ± 0.9, adults; 40.9 ± 3.3, children, P < 0.001 vs. adults). Overall mean concentrations of plasma kisspeptin were not significantly different between sexes (mean plasma kisspeptin in pmol/L: 39.5 ± 3.2, boys; 44.3 ± 6.3, girls, P = 0.48). In both sexes, concentrations of plasma kisspeptin increased with age to peak concentrations between 9 and 12 years of age, before decreasing beyond 12 years of age to adulthood. Plasma kisspeptin concentrations were highly significantly elevated in both girls and boys aged 9-12 when compared with adults (mean plasma kisspeptin in pmol/L: 59.5 ± 18.3, girls, P < 0.01 vs. adult women; 43.8 ± 6.2, boys, P < 0.001 vs. adult men).. We report that circulating kisspeptin is elevated in both boys and girls when compared with adults. Furthermore both boys and girls may have distinct, age-dependent concentrations of circulating kisspeptin. Further studies may determine if plasma kisspeptin could be used as a clinically useful biochemical marker of reproductive development in children.

Topics: Adolescent; Adult; Age Factors; Biomarkers; Child; Child, Preschool; Female; Humans; Kisspeptins; Male; Puberty, Precocious; Radioimmunoassay; Reproduction

The genetic background of idiopathic central precocious puberty (ICPP) is not well understood. The genetic activation of pubertal onset is thought to arise from the effect of multiple genes. Familial ICPP has been reported suggesting the existence of monogenic causes of ICPP. Kisspeptin and its receptor are found to be involved in gonadotropin-releasing hormone (GnRH) secretion and puberty onset. Mutations in their genes, KISS1 and KISSR, have been suggested to be causative for ICPP.. ICPP was defined by pubertal onset before 8 years of age in girls, and a pubertal luteinizing hormone (LH) response to GnRH testing. Twenty-eight girls with ICPP were included in the study [age at diagnosis was 5.72±2.59, with a mean bone age advancement of 1.4 years (-0.1 to 2.8). Height at onset of therapy in SD score was 0.90±1.48 for age]. Luteinizing hormone-releasing hormone test was performed in all subjects, and all of them had a pubertal response (LH 20.35±32.37 mIU/mL; FSH 23.32±15.72 mIU/mL). The coding regions of KISS1 and KISS1R were sequenced.. No rare variants were detected in KISS1 or KISS1R in the 28 subjects with ICPP.. We confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.

Topics: Child; Female; Humans; Kisspeptins; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1

Kisspeptin/G-protein couple receptor-54 (GPR54) system plays a key role in the activation of the gonadotropic axis at puberty. Central precocious puberty (CPP) is caused by the premature activation of hypothalamic gonadotropin-releasing hormone secretion. This study was aimed to identify KISS1 gene variations and to investigate the associations between KISS1 gene variations and CPP in Korean girls. All coding exons of KISS1 gene were sequenced in Korean girls with CPP (n = 143) and their healthy controls (n = 101). Nine polymorphisms were identified in KISS1 gene. A novel single-nucleotide polymorphism (SNP), 55648176 T/G, was identified for the first time. SNP 55648184 C/G and 55648186 -/T were detected more frequently in CPP group than in control group. SNP 55648176 T/G was detected less frequently in CPP group than in control group. Haplotype GGGC-ACCC was detected less frequently in CPP group. The genetic variations of KISS1 gene can be contributing factors of development of CPP. The association between the gene variations and CPP should be validated by further evidence obtained from large-scaled and functional studies.

Topics: Base Sequence; Child; Female; Genetic Markers; Genetic Predisposition to Disease; Humans; Kisspeptins; Molecular Sequence Data; Point Mutation; Polymorphism, Single Nucleotide; Prevalence; Puberty, Precocious; Reproducibility of Results; Republic of Korea; Risk Assessment; Sensitivity and Specificity

Is there an association between exposure to phthalates and the timing of female puberty?. Our study suggests that the early onset of puberty is related to increased kisspeptin secretion.. Girls are maturing earlier than in past decades and the quantity of phthalates used in consumer products has concurrently risen. The hypothesis that exposure to phthalates may increase kisspeptin secretion and thereby cause early-onset puberty is unexplored.. This case-control study ran from 2006 to 2009. We enrolled 104 girls. Girls in the central precocious puberty (CPP) (case) group were recruited from a pediatric endocrinology policlinic in Taiwan; prepubescent controls were recruited from local elementary schools and all were categorized based on a pediatrician's diagnosis.. The physical characteristics of puberty were assessed and levels of LH, FSH estradiol and kisspeptin-54 in blood samples were evaluated using radioimmunoassay. Reversed-phase high-performance liquid chromatography-tandem mass spectrometry was used to analyze seven urinary phthalate metabolites. Non-parametric analyses, trend tests and linear regressions were performed on the data.. All seven urinary phthalate metabolites in the CPP group were significantly (P < 0.05) higher than in prepubescent controls. Serum kisspeptin-54 levels were higher (P = 0.022) in the CPP group than controls and were still significantly higher after adjusting for age (P = 0.03). There was a significant increasing trend (P(trend) = 0.005) between levels of kisspeptin and the stages of puberty. The concentration of kisspeptin-54 did not change in girls treated with leuprorelin acetate. There was a significant positive correlation between kisspeptin-54 and urinary mono-n-butyl phthalate (ng/ml: R(2) = 0.251, P < 0.001; μg/g-creatinine: R(2) = 0.109, P = 0.024).. The study duration was short and the sample size relatively small; therefore, we were unable to collect sufficient evidence to support the temporality between exposure to phthalates and the subsequent occurrence of PP.. Kisspeptin may promote the onset of puberty in girls who are exposed to a high level of phthalates, especially di-n-butyl phthalate. These data suggest that developing a kisspeptin antagonist might be an alternative strategy for treating PP.. This work was supported by grants NSC 96-2621-Z-006-013 and NSC 97-2621-M-006-001 from the Taiwan National Science Council. The authors have no conflicts of interest to disclose.

Topics: Adolescent; Case-Control Studies; Child; Creatinine; Female; Humans; Kisspeptins; Linear Models; Phthalic Acids; Puberty, Precocious

Hypothalamic neurons, which produce the kisspeptin family of peptide hormones (Kp), are critical for initiating puberty and maintaining estrous cyclicity by stimulating gonadotropin-releasing hormone (GnRH) release. Conversely, RFamide-related peptide-3 (RFRP3) neurons inhibit GnRH activity. It has previously been shown that neonatal exposure to bisphenol A (BPA) can alter the timing of female pubertal onset and induce irregular estrous cycles or premature anestrus. Here we tested the hypothesis that disrupted ontogeny of RFamide signaling pathways may be a mechanism underlying advanced puberty. To test this, we used a transgenic strain of Wistar rats whose GnRH neurons express enhanced green fluorescent protein. Pups were exposed by daily subcutaneous injection to vehicle, 17beta-estradiol (E2), 50 μg/kg BPA, or 50 mg/kg BPA, from Postnatal Day (PND) 0 through PND 3, and then cohorts were euthanized on PNDs 17, 21, 24, 28, and 33 (5-8 animals per age per exposure; males were collected on PNDs 21 and 33). Vaginal opening was advanced by E2 and 50 μg/kg BPA. On PND 28, females exposed to E2 and 50 μg/kg BPA had decreased RFRP-3 fiber density and contacts on GnRH neurons. RFRP3 perikarya were also decreased in females exposed to 50 μg/kg BPA. Data suggest that BPA-induced premature puberty results from decreased inhibition of GnRH neurons.

Topics: Animals; Benzhydryl Compounds; Body Weight; Estrogens, Non-Steroidal; Female; Gonadotropin-Releasing Hormone; Hypothalamus; Kisspeptins; Male; Neuropeptides; Phenols; Puberty, Precocious; Rats; Rats, Transgenic; Rats, Wistar; Vagina

Premature thelarche (PT) is defined as isolated breast development without secondary sex characteristics in girls below the age of eight. We aimed to determine whether the level of kisspeptin, which plays a role in the release of gonadotropins, is associated with PT.. The patient group included children with PT aged 3-8 years (n=20) and the control group included healthy children in the same age range (n=20). Height standard deviation scores (HSDSs), bone maturation and growth velocity were evaluated in the two groups. Basal follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), and sex hormone-binding globulin (SHBG) levels were also measured in the two groups by immunochemiluminometric assay (ICMA). A gonadotropin-releasing hormone (GnRH) test was also conducted in the patient group and the peak levels of FSH and LH were determined. Kisspeptin levels were measured using enzyme immunoassay (EIA).. No differences were found between the groups in terms of age, HSDS, annual growth rate and bone age. While the plasma basal FSH, LH and E2 levels in the patient and control groups did not show statistically significant differences, PRL levels were higher in the patient group (p<0.05). Peak LH response to GnRH test was at the prepubertal level (<5 ng/mL) in patients with PT. In the patient group, kisspeptin levels were significantly higher compared to the levels in the control group (2.96 ± 1.21 ng/dL vs. 1.19 ± 0.41 ng/dL, p<0.05), and kisspeptin levels showed a significant correlation with PRL, FSH, LH, and E2 levels (p<0.05).. In this study, plasma kisspeptin levels were found to be higher in patients with PT and to show a positive correlation with increased PRL levels. Kisspeptin is one of the neuropeptides that plays a role in the onset of puberty. Our results support the hypothesis that PT may result from the temporary activation of central stimulants.

Topics: Age Determination by Skeleton; Breast; Child; Child, Preschool; Estradiol; Female; Follicle Stimulating Hormone; Humans; Immunoenzyme Techniques; Kisspeptins; Luteinizing Hormone; Prolactin; Puberty, Precocious; Sex Hormone-Binding Globulin

Onset of puberty is dependent on pulsatile secretion of gonadotropin releasing hormone (GnRH). The kisspeptin-GPR54 signaling system has a considerable role in GnRH physiology and induction of puberty.. To evaluate kisspeptin levels in girls with central precocious puberty (CPP) at the time of the diagnosis and during follow-up, to determine whether or not kisspeptin may serve as a marker for diagnosis and follow-up of CPP.. Kisspeptin levels of 28 girls with CPP were measured at the time of diagnosis and repeated at the 6th month of therapy after complete pubertal suppression and compared to kisspeptin levels of 13 age-matched prepubertal controls.. Kisspeptin levels of girls with CPP (10.2 +/- 2.6 pg/mL) were higher than those in controls (8.6 +/- 1.5 pg/mL (p = 0.019). There was a significant decline in the kisspeptin levels (7.3 +/- 1.3 pg/mL) of girls with CPP after pubertal suppression (p < 0.0001).. These findings suggest that kisspeptin levels can be used as corroborative evidence for diagnosis of CPP and a valuable parameter for monitoring treatment efficacy.

Topics: Case-Control Studies; Child; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Prognosis; Puberty; Puberty, Precocious

Central precocious puberty (CPP) is caused by premature activation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin and G-protein coupled receptor-54 system is the essential gatekeeper of the reproductive system, playing a key role in the activation of the gonadotropic axis at puberty. We aimed to determine whether serum kisspeptin may function as a marker for CPP by investigating serum kisspeptin levels in Korean girls with CPP and their prepubertal controls. Serum kisspeptin levels of Korean girls with CPP (n = 30) and age-matched healthy prepubertal controls (n = 30) were measured with a competitive enzyme immunoassay. Serum kisspeptin levels were significantly higher in CPP group than in control group (4.61 ± 1.78 vs 2.15 ± 1.52 pM/L, P < 0.001). Serum kisspeptin was positively correlated with peak luteinizing hormone (LH), peak/basal LH ratio and peak LH/follicular-stimulating hormone (FSH) ratio during GnRH stimulation test. CPP is supposed to be triggered by premature increase of kisspeptin. Serum kisspeptin may be used as a marker of CPP. Further studies on KISS1 gene polymorphisms leading to higher risk of premature increase of kisspeptin and upstream regulator of kisspeptin are also needed.

Topics: Biomarkers; Child; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Puberty, Precocious; Republic of Korea; Tumor Suppressor Proteins

The system KISS1-KISS1R is one of the main regulators of the hypothalamic-pituitary-gonadal axis and constitutes a link between metabolism and reproduction through its interaction with leptin. The aim of this study was to clarify the possible utility of kisspeptin as a pubertal marker and/or the possible influence of nutritional status in kisspeptin levels. To this end, we have studied kisspeptin plasma levels throughout sexual development and in prepubertal obese girls and girls affected by idiopathic central precocious puberty (CPP). Plasma kisspeptin concentrations were analyzed by RIA. An increase in kisspeptin levels was observed in adult females compared to healthy prepubertal and pubertal girls (p<0.001) and to adult males (p<0.001). Additionally, kisspeptin was increased in prepubertal obese girls compared to healthy prepubertal girls (p<0.01) and girls with idiopathic CPP (p<0.05). As revealed by the regression analysis, in prepubertal healthy and obese girls and girls with idiopathic CCP, the parameters that influenced kisspeptin levels were BMI (R(2)=0.10, p<0.05) and leptin levels (R(2)=0.14, p<0.01). In conclusion, kisspeptin levels do not seem to be a good pubertal marker. The results obtained in prepubertal and idiopathic CCP girls point to a relationship between leptin, BMI and kisspeptin at least in this group, and suggest a possible role for adipose tissue in the modulation kisspeptin synthesis.

Topics: Adolescent; Adult; Biomarkers; Body Mass Index; Case-Control Studies; Child; Cross-Sectional Studies; Female; Humans; Kisspeptins; Leptin; Male; Obesity; Puberty; Puberty, Precocious; Regression Analysis; Young Adult

Topics: Body Mass Index; Body Weight; Female; Humans; Kisspeptins; Puberty, Precocious; Tumor Suppressor Proteins

The present study aims to investigate the effect of nourishing "Yin"-removing "Fire" herbal mixture, a Chinese herb-based formulation, on hypothalamic kisspeptin expression in danazol-induced female precocious model rats.. The female Sprague-Dawley rats were divided into intact normal (N), central precocious puberty (CPP) model (M), vehicle without CPP (V), CPP model exposed to herbal mixture (HM) and CPP model exposed to saline (S) groups. At postnatal day 5, a single subcutaneous injection of 300 microg of danazol was administered to induce CPP model rats. From P15, rats in the HM group were continuously gavaged with the 1 ml/50 g body weight mixture, until two consecutive regular estrous cycles were established. The hypothalamic Kiss-1 expression was detected by RT-PCR and immunohistochemistry.. The day of vaginal opening and establishment of two regular estrous cycles were delayed in the HM group compared with M and S groups (P<0.05, respectively). The level of hypothalamic Kiss-1 mRNA and the number of kisspeptin-immunoreactive (kisspeptin-ir) cells in the arcuate nucleus (ARC), preoptic area (POA) and periventricular nucleus (PeN), were decreased significantly in the HM group compared with the M and S groups (P<0.01, respectively) on the day of onset-puberty.. These results indicate that the kisspeptin signaling pathway might be involved in the effect of herbal mixture treatment on CPP.

Topics: Animals; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Female; Hypothalamus; Kisspeptins; Ovary; Proteins; Puberty, Precocious; Rats; Rats, Sprague-Dawley; Up-Regulation; Uterus

Kisspeptin, encoded by the KISS1 gene, is a key stimulatory factor of GnRH secretion and puberty onset. Inactivating mutations of its receptor (KISS1R) cause isolated hypogonadotropic hypogonadism (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP).. Our objective was to investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH.. Eighty-three children with CPP (77 girls) and 61 patients with IHH (40 men) were studied. The control group consisted of 200 individuals with normal pubertal development.. The promoter region and the three exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetic human wild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells.. Two novel KISS1 missense mutations, p.P74S and p.H90D, were identified in three unrelated children with idiopathic CPP. Both mutations were absent in 400 control alleles. The p.P74S mutation was identified in the heterozygous state in a boy who developed CPP at 1 yr of age. The p.H90D mutation was identified in the homozygous state in two unrelated girls with CPP. In vitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-type and mutant kp54 in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared with the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group.. Two KISS1 mutations were identified in unrelated patients with idiopathic CPP. The p.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggesting a role for this mutation in the precocious puberty phenotype.

Topics: Exons; Female; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Infant; Kisspeptins; Male; Mutation; Penis; Puberty; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Tumor Suppressor Proteins

Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor alpha (TGFalpha), and GRM1A, which encodes the type 1 metabotropic glutamate receptor alpha isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release.. Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFalpha, KISS1, GPR54, and GRM1A.. Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFalpha, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP.. Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.

Topics: Adolescent; Child; Child, Preschool; Female; Gene Expression; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Infant; Kisspeptins; Male; Puberty, Precocious; Radiography; Receptors, LHRH; Seizures; Transforming Growth Factor alpha; Tumor Suppressor Proteins

Mutations in the GPR54 gene have already been identified as a cause of idiopathic hypogonadotrophic hypogonadism and central precocious puberty (CPP) in certain patients. However, currently there is only a limited amount of data available regarding KISS1 gene mutations or polymorphisms. The aim of this study is to identify KISS1 gene mutations or polymorphisms in Korean girls with CPP. 101 Korean girls with CPP were recruited as the patient group, and 51 healthy Korean female adults as the control group. All coding exons and exon-intron boundaries of the KISS1 gene were sequenced. The relationships between identified sequence variations and CPP were evaluated via the comparison of allele frequencies between the two groups. Different clinical characteristics were also compared between the subgroups with or without a certain variation in the patient group. Eight polymorphisms were identified in the KISS1 gene. Although two of them were novel, those polymorphisms could not lead to amino acid changes. p.P110T was detected less frequently in CPP patients than in the controls (P = 0.022). Moreover, the CPP patients with p.P110T evidenced lower peak FSH values under GnRH stimulation than those without p.P110T (P = 0.002). The allele frequencies of several polymorphisms in the Korean population were identified in this study. An infrequent polymorphism in the KISS1 gene, p.P110T, appeared to be meaningful. This polymorphism was suggested to exert a protective effect on pubertal precocity, even though more evidence will be required to confirm the accurate function.

Topics: Adolescent; Adult; Base Sequence; Child; DNA; Exons; Female; Follicle Stimulating Hormone; Gene Frequency; Gonadotropin-Releasing Hormone; Humans; Introns; Kisspeptins; Luteinizing Hormone; Polymerase Chain Reaction; Polymorphism, Genetic; Puberty, Precocious; Republic of Korea; Sequence Analysis, DNA; Tumor Suppressor Proteins

Central precocious puberty (CPP) causes early epiphyseal maturation, and early initiation of treatment improves final height. Unfortunately, there is no one parameter that can distinguish CPP from premature thelarche (PT), which is self-limited and requires no therapy. In animal models, kisspeptin, the ligand for the G-protein coupled receptor GPR54, was found to induce precocious activation of the gonadotrophic axis. Data on kisspeptin levels in girls with precocious puberty or in healthy prepubertal girls are lacking. We measured blood kisspeptin levels in girls with CPP and evaluated its potential as a clinical marker for CPP. Design This was a case-control study.. Thirty-one girls clinically diagnosed with CPP and 14 prepubertal age-matched healthy controls. Measurements Kisspeptin blood levels.. Kisspeptin levels were significantly higher in the girls with CPP than in the controls: 14.62 +/- 10.2 pmol/l vs. 8.35 +/- 2.98 pmol/l, P < 0.05. Within the CPP group, there were no significant differences between the girls with a peak LH >5.0 IU/l and those with a peak LH

Topics: Case-Control Studies; Female; Humans; Kisspeptins; Puberty, Precocious; Tumor Suppressor Proteins

Hypothalamic hamartomas (HHs) are congenital lesions composed of neurons and astroglia. Frequently, HHs cause central precocious puberty (CPP) and/or gelastic seizures. Because HHs might express genes similar to those required for the initiation of normal puberty, we used cDNA arrays to compare the gene expression profile of an HH associated with CPP with three HHs not accompanied by sexual precocity.. Global changes in gene expression were detected using Affymetrix arrays. The results were confirmed by semiquantitative PCR, which also served to examine the expression of selected genes in the hypothalamus of female monkeys undergoing puberty.. All HHs were associated with seizures. Ten genes whose expression was increased in the HH with CPP were identified. They encode proteins involved in three key cellular processes: transcriptional regulation, cell-cell signaling, and cell adhesiveness. They include IA-1 and MEF2A, two transcription factors required for neuronal development; mGluR1 and VILIP-1, which encode proteins involved in neuronal communication, and TSG-6 that encodes a protein involved in cell adhesiveness. Of these, expression of mGluR1 also increases in the female monkey hypothalamus at puberty.. Increased expression of these genes in HHs may be relevant to the ability of some HHs to induce sexual precocity.

Topics: Adolescent; Adult; Animals; Cell Adhesion Molecules; Child; Child, Preschool; DNA-Binding Proteins; Female; Gene Expression Profiling; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Kisspeptins; Macaca mulatta; Male; Oligonucleotide Array Sequence Analysis; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, Metabotropic Glutamate; Repressor Proteins; Sexual Maturation; Transforming Growth Factor alpha; Tumor Suppressor Proteins

Gonadotropin-dependent, or central, precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis. In girls, this condition is most often idiopathic. Recently, a G protein-coupled receptor, GPR54, and its ligand, kisspeptin, were described as an excitatory neuroregulator system for the secretion of gonadotropin-releasing hormone (GnRH). In this study, we have identified an autosomal dominant GPR54 mutation--the substitution of proline for arginine at codon 386 (Arg386Pro)--in an adopted girl with idiopathic central precocious puberty (whose biologic family was not available for genetic studies). In vitro studies have shown that this mutation leads to prolonged activation of intracellular signaling pathways in response to kisspeptin. The Arg386Pro mutant appears to be associated with central precocious puberty.

Topics: Amino Acid Sequence; Child; Extracellular Signal-Regulated MAP Kinases; Female; Genes, Dominant; Heterozygote; Humans; Inositol Phosphates; Kisspeptins; Molecular Sequence Data; Phosphorylation; Point Mutation; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Sequence Analysis, DNA; Signal Transduction; Tumor Suppressor Proteins

The kisspeptin/GPR54 pathway has been proven to be crucial in the process of puberty onset, yet the polymorphisms in the KISS1 gene and their relationships with central precocious puberty (CPP) have not been investigated. This study was performed to reveal the relationship between the gene and the disease.. 272 Chinese Han girls diagnosed to be CPP patients were recruited as Case Group I, 43 unrelated African women as Case Group II, and 288 unrelated normal Chinese Han girls as Control Group. Polymorphism scans of the KISS1 gene were performed for the first time by bidirectional resequencing of the whole gene in a subset of the patients, and then by ligase detection reaction some of the polymorphisms identified were typed in the two groups and the respective haplotypes were constructed. The relationships of the typed polymorphisms and the haplotypes with CPP were evaluated by an association study between genotypes and phenotypes.. By resequencing, eight polymorphisms were identified, five of which were typed forming 18 haplotypes. Although one novel nonsynonymous single nucleotide polymorphism substituting one amino acid in kisspeptin (P110T) was found to be statistically related to the disease (P = 0.025), no further supporting evidence has yet been found. The other polymorphisms and all the haplotypes were not found to be related.. The polymorphism scanning and typing of KISS1 uncovered several potentially meaningful polymorphisms, but the conclusion was not solid and further studies are necessary for function validation of these polymorphisms.

Topics: Adult; Amino Acid Sequence; Asian People; Base Sequence; Child; Child, Preschool; DNA Mutational Analysis; Female; Gene Frequency; Genetic Linkage; Humans; Kisspeptins; Middle Aged; Models, Biological; Molecular Sequence Data; Polymorphism, Single Nucleotide; Puberty, Precocious; Tumor Suppressor Proteins