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Objectives The etiology of central precocious puberty (CPP) has expanded with identification of new genetic causes, including the monogenic deficiency of Makorin-Ring-Finger-Protein-3 (MKRN3). We aimed to assess the prevalence of CPP causes and the predictors of genetic involvement in this phenotype. Design A retrospective cohort study for an etiological survey of patients with CPP from a single academic center. Methods All patients with CPP had detailed medical history, phenotyping, and brain magnetic resonance imaging (MRI); those with negative brain MRI (apparently idiopathic) were submitted to genetic studies, mainly DNA sequencing studies, genomic microarray, and methylation analysis. Results We assessed 270 patients with CPP: 50 (18.5%) had CPP-related brain lesions (34 [68%] congenital lesions), whereas 220 had negative brain MRI. Of the latter, 174 (165 girls) were included for genetic studies. Genetic etiologies were identified in 22 patients (20 girls), indicating an overall frequency of genetic CPP of 12.6% (22.2% in boys and 12.1% in girls). The most common genetic defects were MKRN3 , Delta-Like-Non-Canonical-Notch-Ligand-1 (DLK1), and Methyl-CpG-Binding-Protein-2 (MECP2) loss-of-function mutations, followed by 14q32.2 defects (Temple syndrome). Univariate logistic regression identified family history (odds ratio [OR] 3.3; 95% CI 1.3-8.3; P =.01) and neurodevelopmental disorders (OR 4.1; 95% CI 1.3-13.5; P =.02) as potential clinical predictors of genetic CPP. Conclusions Distinct genetic causes were identified in 12.6% patients with apparently idiopathic CPP, revealing the genetic etiology as a relevant cause of CPP in both sexes. Family history and neurodevelopmental disorders were suggested as predictors of genetic CPP. We originally proposed an algorithm to investigate the etiology of CPP including genetic studies. [ABSTRACT FROM AUTHOR]

The productivity of beef cows depends on early reproduction traits such as puberty and has an economic impact on the efficiency of production system. Imprinted genes modulate many important endocrine processes such as growth, the onset of puberty and maternal reproductive and behavior. The role of imprinted genes in puberty is a challenging subject since they show the reciprocal role of maternal and paternal genomes in progeny. Although, there are evidences of the involvement of imprint genes in puberty in human, the role of this type of genes in the onset of puberty in cattle has not been studied yet. Here we examined the expression of 27 imprinted genes in pre and post puberty in a bovine model to find differentially expressed imprinted genes in maternal-paternal purebreds and reciprocal crosses across eight tissues and discussed the task of these genes in this crucial process of development and in onset of puberty. DLK1 and MKRN3 that previously described as cause of the central precocious puberty (CPP) in human were differentially expressed in this study. Functional annotation analysis of differentially imprinted genes in different tissues showed significant biological processes of cellular response to growth factor stimulus, response to growth factor, response to parathyroid hormone, developmental growth and the importance of alternative splicing. The results of this study have implications in understanding the role of imprinted genes in the onset of puberty in cattle. [ABSTRACT FROM AUTHOR]

Central precocious puberty (СPP) is caused by premature reactivation of the hypothalamic–pituitary–gonadal axis. Genetic, epigenetic, and environmental factors play a crucial role in determining the timing of puberty. In recent years, the KISS1, KISS1R, MKRN3, and DLK1 variants have been identified as hereditary causes of CPP. The MKRN3 and DLK1 genes are imprinted, and therefore epigenetic modifications that alter the expression of these genes are also considered as a cause of precocious puberty. With the progression of CPP, epigenetic factors such as DNA methylation, posttranslational modifications of histones and noncoding RNAs can mediate the relationship between the influence of genetic variants and the environment. CPP is also associated with other short- and long-term adverse health effects. This is the basis for research aimed at understanding the genetic and epigenetic causes of СPP. The purpose of this review is to summarize the published data on the molecular genetic and epigenetic mechanisms of the formation of СPP. [ABSTRACT FROM AUTHOR]

The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP. [ABSTRACT FROM AUTHOR]

Context Idiopathic central precocious puberty (iCPP) is defined by the premature reactivation of the hypothalamic-pituitary-gonadal axis with normal magnetic resonance imaging scan of the central nervous system, causing the development of secondary sexual characteristics before age 8 years in girls and 9 years in boys. MKRN3 loss of function variants now represent the most common genetic cause of iCPP. Objective This work aims to document the clinical course of puberty in 8 families harboring pathogenic MKRN3 variants. Methods This is an observational case series study of patients with CPP due to MKRN3 variants followed in a single center. Results Genetic analysis of MKRN3 was carried out in 28 unrelated patients with iCPP and a family history of paternal inheritance or no/unavailable maternal inheritance, particularly in case of very early and rapidly evolving CPP. We identified 6 novel and 2 recently described variants in the MKRN3 gene in 9 girls, 1 boy, and their family members. These mutations were all predicted to be deleterious by in silico prediction programs Conclusion We have identified 6 novel MKRN3 mutations in children with CPP. An MKRN3 loss of function should be considered after careful history pinpointing paternally inherited CPP. A family segregation study allowed the detection of an MKRN3 variant in 2 young brothers still prepubertal, raising the question of screening and management of asymptomatic prepubertal family members. [ABSTRACT FROM AUTHOR]

Central precocious puberty (CPP) is a condition in which the hypothalamus--pituitary--gonadal system is activated earlier than the normal developmental stage. The etiology includes organic lesions in the brain; however, in the case of idiopathic diseases, environmental and/or genetic factors are involved in the development of CPP. A genetic abnormality in KISS1R, that encodes the kisspeptin receptor, was first reported in 2008 as a cause of idiopathic CPP. Furthermore, genetic alterations in KISS1, MKRN3, DLK1, and PROKR2 have been reported in idiopathic and/or familial CPP. Of these, MKRN3 has the highest frequency of pathological variants associated with CPP worldwide; but, abnormalities in MKRN3 are rare in patients in East Asia, including Japan. MKRN3 and DLK1 are maternal imprinting genes; thus, CPP develops when a pathological variant is inherited from the father. The mechanism of CPP due to defects in MKRN3 and DLK1 has not been completely clarified, but it is suggested that both may negatively control the progression of puberty. CPP due to such a single gene abnormality is extremely rare, but it is important to understand the mechanisms of puberty and reproduction. A further development in the genetics of CPP is expected in the future. [ABSTRACT FROM AUTHOR]

Objective: To compared the incidence rates and clinical features of precocious girls before and during the COVID-19 pandemic among Shanghai school-aged girls, and explored the potential mechanisms. Methods: This cross-sectional study collected medical data about precocious girls between 2016 and 2020 from Shanghai Children's Medical Center. Data of inpatient precocious girls from March to August in 2016-2019 (n=246) and 2020 (n=237) were collected. Subjects with abnormal brain and pituitary gland MRI reports, other endocrine diseases or chronic diseases were excluded. Finally, 209 precocious girls were included in the 2016-2019 group and 191 precocious girls were include in the 2020 group. Monthly incidence rates and clinical features were compared between before and during the COVID-19 pandemic. Linear regression models were used to examine the associations between biomarkers to explore the potential mechanisms. Results: Monthly incidence rates of precocious puberty in outpatient girls from March to December 2020 (0.44-1.36%) and in inpatient girls from March to August 2020 (27.04-47.83%) were higher than those in 2016-2019 (0.30-0.52% and 10.53-18.42%, respectively). Serum concentrations of GnRH were higher in the 2020 group than in the 2016-2019 group (2.81 vs 1.99 mg/L). Serum concentrations of MKRN3 (1.02 vs 1.93 ng/ml) and ghrelin (0.38 vs 0.88 ng/ml) were lower in the 2020 group than in the 2016-2019 group. Moreover, the serum concentration of ghrelin was positively associated with the serum concentration of MKRN3 [ β= 0.891 (95% CI , 0.612, 1.171); p< 0.001]. Conclusions: These findings suggest an increased incidence of precocious puberty during the COVID-19 pandemic among Shanghai school-aged girls, which may be associated with decreased serum concentrations of MKRN3 and ghrelin, and indicated ghrelin as a potential regulatory mechanism of puberty. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ObjectiveTo compared the incidence rates and clinical features of precocious girls before and during the COVID-19 pandemic among Shanghai school-aged girls, and explored the potential mechanisms.MethodsThis cross-sectional study collected medical data about precocious girls between 2016 and 2020 from Shanghai Children’s Medical Center. Data of inpatient precocious girls from March to August in 2016-2019 (n=246) and 2020 (n=237) were collected. Subjects with abnormal brain and pituitary gland MRI reports, other endocrine diseases or chronic diseases were excluded. Finally, 209 precocious girls were included in the 2016-2019 group and 191 precocious girls were include in the 2020 group. Monthly incidence rates and clinical features were compared between before and during the COVID-19 pandemic. Linear regression models were used to examine the associations between biomarkers to explore the potential mechanisms.ResultsMonthly incidence rates of precocious puberty in outpatient girls from March to December 2020 (0.44-1.36%) and in inpatient girls from March to August 2020 (27.04-47.83%) were higher than those in 2016-2019 (0.30-0.52% and 10.53-18.42%, respectively). Serum concentrations of GnRH were higher in the 2020 group than in the 2016-2019 group (2.81 vs 1.99 mg/L). Serum concentrations of MKRN3 (1.02 vs 1.93 ng/ml) and ghrelin (0.38 vs 0.88 ng/ml) were lower in the 2020 group than in the 2016-2019 group. Moreover, the serum concentration of ghrelin was positively associated with the serum concentration of MKRN3 [β=0.891 (95% CI, 0.612, 1.171); p

Background: 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 MKRN3 , DLK1 , KISS1 , and KISS1R genes were investigated in patients with CPP. Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed. Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Central precocious puberty (CPP) is one of the most common and complex problems in clinical pediatric endocrinology practice. Mutation of the MKRN3 gene can cause familial CPP. Methods and Results: Here we reported a Chinese patient bearing a novel MKRN3 mutation (c.G277A/p.Gly93Ser) and showing the CPP phenotype. Functional studies found that this mutation of MKRN3 attenuated its autoubiquitination, degradation, and inhibition on the transcriptional activity of GNRH1, KISS1 , and TAC3 promoters. Conclusion: MKRN3 (Gly93Ser) is a loss-of-function mutation, which attenuates the inhibition on GnRH1-related signaling, suggesting that this mutant can lead to central precocious puberty. [ABSTRACT FROM AUTHOR]

Context: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP).Objective: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects.Methods: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group.Results: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization.Conclusion: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels. [ABSTRACT FROM AUTHOR]

Introduction: Loss-of-function mutation of MKRN3 represents the most frequent genetic cause of familial central precocious puberty (CPP). The outcomes of gonadotropin-releasing hormone analog (GnRHa) treatment in CPP patients with MKRN3 defects are unknown. Objective: To describe the clinical and hormonal features of patients with CPP with or without MKRN3 mutations after GnRHa treatment. Anthropometric, metabolic and reproductive parameters were evaluated. Patients and Methods: Twenty-nine female patients with CPP due to loss-of-function mutations in the MKRN3 and 43 female patients with idiopathic CPP were included. Their medical records were retrospectively evaluated for clinical, laboratory, and imaging study, before, during, and after GnRHa treatment. All patients with idiopathic CPP and 11 patients with CPP due to MKRN3 defects reached final height (FH). Results: At the diagnosis, there were no significant differences between clinical and laboratory features of patients with CPP with or without MKRN3 mutations. A high prevalence of overweight and obesity was observed in patients with CPP with or without MKRN3 mutations (47.3 and 50%, respectively), followed by a significant reduction after GnRHa treatment. No significant differences in the values of mean FH and target height were found between the 2 CPP groups after GnRHa treatment. Menarche occurred at the expected age in patients with or without CPP due to MKRN3 mutations (11.5 ± 1.3 and 12 ± 0.6 years, respectively). The prevalence of polycystic ovarian syndrome was 9.1% in patients with CPP due to MKRN3 mutations and 5.9% in those with idiopathic CPP. Conclusion: Anthropometric, metabolic, and reproductive outcomes after GnRHa treatment were comparable in CPP patients, with or without MKRN3 mutations, suggesting the absence of deleterious effects of MKRN3 defects in young female adults' life. [ABSTRACT FROM AUTHOR]

A critical body weight is necessary for pubertal development, an effect mediated in part by leptin. The potential regulation by leptin of Makorin Ring Finger Protein 3 (MKRN3) , in which loss-of-function mutations are the most common genetic cause of central precocious puberty, has not been previously explored. In mice, expression of Mkrn3 in the hypothalamic arcuate nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if leptin contributes to the decrease in hypothalamic Mkrn3 mRNA levels observed in mice during pubertal development. We first used a leptin-deficient (ob/ob) mouse model. Mkrn3 mRNA levels in the mediobasal hypothalamus (MBH), which includes the arcuate nucleus, and in the preoptic area (POA), both showed a significant decrease with age from postnatal day (PND) 12 to PND30 in ob/ob mice in both males and females, similar to that observed in wild-type mice. To further explore the effects of leptin on Mkrn3 expression, we exposed prepubertal wild-type mice to high levels of leptin from age PND9-12, which did not result in any significant difference in Mkrn3 expression levels in either the MBH or POA. In summary, regulation of Mkrn3 expression by leptin was not observed in either the MBH or the POA, 2 hypothalamic sites important for pubertal maturation. These data suggest that the decline in Mkrn3 at the onset of puberty may occur independently of leptin and support our hypothesis that MKRN3 is a bona fide controller of puberty initiation. [ABSTRACT FROM AUTHOR]

Central precocious puberty (CPP) refers to a human syndrome of early puberty initiation with characteristic increase in hypothalamic production and release of gonadotropin-releasing hormone (GnRH). Previously, loss-of-function mutations in human MKRN3 , encoding a putative E3 ubiquitin ligase, were found to contribute to about 30% of cases of familial CPP. MKRN3 was thereby suggested to serve as a 'brake' of mammalian puberty onset, but the underlying mechanisms remain as yet unknown. Here, we report that genetic ablation of Mkrn3 did accelerate mouse puberty onset with increased production of hypothalamic GnRH1. MKRN3 interacts with and ubiquitinates MBD3, which epigenetically silences GNRH1 through disrupting the MBD3 binding to the GNRH1 promoter and recruitment of DNA demethylase TET2. Our findings have thus delineated a molecular mechanism through which the MKRN3–MBD3 axis controls the epigenetic switch in the onset of mammalian puberty. [ABSTRACT FROM AUTHOR]

Puberty is a critical period of development regulated by genetic, nutritional, and environmental factors. The role of makorin ring finger protein 3 ( MKRN3 ) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP). To date, MKRN3 mutations are the most common known genetic cause of CPP. MKRN3 is a member of the makorin family of ubiquitin ligases, together with MKRN1 and MKRN2. The Mkrn genes have been identified in both vertebrates and invertebrates and show high evolutionary conservation of their gene and protein structures. While the existence of Mkrn orthologues in a wide spectrum of species suggests a vital cellular role of the makorins, their role in puberty initiation and endocrine functions is just beginning to be investigated. In this review, we discuss recent studies that have shown the involvement of Mkrn3 and other makorins in the regulation of pubertal development and other endocrine functions, including metabolism and fertility, as well as their underlying mechanisms of action. [ABSTRACT FROM AUTHOR]

Background: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. Methods: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2–8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. Results: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). Conclusions: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa. [ABSTRACT FROM AUTHOR]

Background: Little is known about the genetic causes responsible for idiopathic central precocious puberty (iCPP). More recently, described loss-of-function mutations in the makorin ring finger protein 3 (MKRN3) gene have been dem-onstrated to be involved in the pathogenesis of familial iCPP. Aim: The objective of this study was to investigate the potential role of MKRN3 in patients with familial iCPP. Methods: We investigated potential sequence variations in the maternal imprinted MKRN3 gene using Next Generation Sequencing (NGS) analysis in 31 participants from 2 families (6 participants were diagnosed with familial iCPP on the basis of clinical and hormonal findings). Six patients diagnosed with familial iCPP and their unaffected first- and second-degree relatives, including their grandparents, were screened for MKRN3 gene variants. Results: Two heterozygous frameshift mutations (c.441_441delG, p.H148Tfs*23 and c803_803delAT, p.M268Vfs*23) were described in the MKRN3 gene in 2 probands with familial iCPP and in some of their family members. These frameshift mutations create a premature stop codon and result in a truncated protein. Conclusions: Our report further expands the MKRN3 gene mutation spectrum in patients with familial iCPP. Screening for potential MKRN3 variants should be performed in patients with familial iCPP as well as in patients with sporadic iCPP. [ABSTRACT FROM AUTHOR]

The article discusses a study of the makorin ring finger 3 gene in girls with idiopathic central precocious puberty (CPP) where 105 Taiwanese girls presented with idiopathic CPP from 105 unrelated families were recruited. The findings demonstrated the new idiopathic CPP cases with MKRN3 mutations, uncovered 3 novel missense mutations within MKRN3 and supported the hypothesis that this gene is one critical factor in the control of puberty development.

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. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]