Статті в журналах: "MKRN3"

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Naulé, Lydie, and Ursula B. Kaiser. "Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions." Seminars in Reproductive Medicine 37, no. 04 (July 2019): 166–73. http://dx.doi.org/10.1055/s-0039-3400965.

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AbstractPuberty 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.

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Chen, Ting, Linqi Chen, Haiying Wu, Rongrong Xie, Fengyun Wang, Xiuli Chen, Hui Sun, and Fei Xiao. "Low Frequency of MKRN3 and DLK1 Variants in Chinese Children with Central Precocious Puberty." International Journal of Endocrinology 2019 (October 3, 2019): 1–6. http://dx.doi.org/10.1155/2019/9879367.

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Background. Central precocious puberty (CPP) is defined by gonadotropin-dependent development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. MKRN3 and DLK1 are two genes, disease-causing variants of which have recently been discovered to cause idiopathic CPP. Methods. We screened 173 Chinese patients (9 males and 164 females; 9 familial and 164 sporadic) with ICPP and 43 patients (9 males and 34 females; 3 familial and 40 sporadic) with early puberty for variants in MKRN3. We also screened 19 patients with ICPP and early puberty for variants of DLK1 (17 males and 2 females; 5 familial and 14 sporadic). Results. We identified four novel missense variants of MKRN3, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. According to ACMG standards, two MKRN3 variant (p.Glu380Lys and p.Ile357Met) are likely pathogenic, and two others are of uncertain significance. We also performed bioinformatic analysis to evaluate the impact of variants on MKRN3 protein structures, which showed that Ile357Met locates at the zinc-binding region (C3HC4 RING finger motif), while Glu380Lys is spatially extremely close to the C3HC4 RING finger, MKRN-specific Cys-His domain, and the third C3H1 zinc-finger motif region. Per Glu380Lys, Glu with negative charges has been changed into Lys with positive charges, which may affect the hydrogen bond formation between amino acids and the stability of the local structure, thus affecting the binding of zinc iron to MKRN3 protein. Besides, we did not identify any variants of DLK1 gene in our patients. Conclusions. In this study, we report four novel MKRN3 variants in patients with ICPP. Moreover, we did not find any variants of DLK1 gene. Variants of MKRN3 are relatively uncommon in Chinese ICPP patients.

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Ahmad, Muhammad Jamil, Hafiz Ishfaq Ahmad, Muhammad Muzammal Adeel, Aixin Liang, Guohua Hua, Saeed Murtaza, Riaz Hussain Mirza, Abdelmotaleb Elokil, Farman Ullah, and Liguo Yang. "Evolutionary Analysis of Makorin Ring Finger Protein 3 Reveals Positive Selection in Mammals." Evolutionary Bioinformatics 15 (January 2019): 117693431983461. http://dx.doi.org/10.1177/1176934319834612.

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Makorin ring finger proteins (MKRNs) are part the of ubiquitin-proteasome system; a complex system important for cell functions. Ubiquitin fate through proteolytic, non-proteolytic pathways varies, depending on covalent linkage between ubiquitin and protein substrates. Makorin ring finger protein 3 is an integral part of covalent linkage of ubiquitin to protein substrates. Similar to others imprinted genes, MKRN3 also evolve under positive selection; however, which codons are specifically selected in MKRN3 during evolution are needed to be explored. Different maximum-likelihood (ML) codon-based methodologies were used to ascertain positive selection signatures in 22 mammalian sequences of MKRN3 to probe an individual codon for positive selection signatures. By applying the HyPhy software package implemented in the Data Monkey Web Server and CODEML implemented in PAML, evolutionary analysis based on two Ml frameworks were conducted. The analysis was executed by comparing M1a against M2a, M7 against M8, and PAML models and 2∆Lnl ( LRT) was resulted by likelihood logs. M1a contributed ω1 ( dN/dS) with LRT value ( ∆Lnl) 12.01, and positive selection was found in M2a with ω3 = 2.23603. To further improve selection test, M8 was compared to M7 with 2∆ Lnl ( LRT) 30.17, and M8 showed positive selection with ω = 1.55759. The data were fit to M8 than M7, which suggests that M8 was the most significant model of selection. M8 was judged encouraging for this analysis and used to establish a positive selection of MKRN3 proteins. We found Gly312 as a positively selected amino acid in a zinc finger motif/Really Interesting New Gene (RING) finger motif; the former ones’ region is involved in RNA binding and the later ones in ubiquitin ligase activity of the protein, vital for protein function. Selection analyses of MKRNs might advance the developments in unique approaches that could lead to genetic progress over the selection of superior individuals with the breeding values higher for certain traits as ancestries to get the next generation.

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Abreu, Ana Paula, Rona S. Carroll, Jacob Haase, Ursula B. Kaiser, Iñigo Landa, John C. Magnotto, Lydie Naulé, Manar Zoghdan, and Alessandra Mancini. "OR17-1 MKRN3 Inhibits the Reproductive Axis by Interacting With Key Hypothalamic Substrates and Targeting Neurokinin B to Degradation Pathways." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A616. http://dx.doi.org/10.1210/jendso/bvac150.1277.

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Abstract Background and Objectives Human fertility is attained following puberty due to finely orchestrated events driven by hypothalamic release of the excitatory neuropeptide neurokinin B (NKB), which in turn stimulates the release of kisspeptin and then GnRH to activate the downstream pituitary-gonadal axis. Our group has identified that loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) cause central precocious puberty (CPP). Mkrn3 is highly expressed in the hypothalamus of both male and female mice in early postnatal life, then declines prior to the onset of puberty. Mutations in MKRN3 E3 ubiquitin ligase domain, identified in patients with CPP, result in reduced auto-ubiquitination. However, the mechanisms of action of MKRN3 and its targets remain largely unknown. We hypothesized that MKRN3 inhibits the reproductive axis through interactions with hypothalamic substrates, targeting them to degradation pathways. Methods and Results Using interactome analysis and candidate approaches in vitro, we identified poly(A) binding protein cytoplasmic 1 and 4 (PABPC1 and 4) and insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) as MKRN3 interactors, consistent with reports from other research groups. Additionally, our proteomic analysis revealed that Igf2bp1 levels are increased in the hypothalamus of Mkrn3 knockout (KO) mice versus wild type animals. Remarkably, we found that MKRN3-IGF2BP1 interaction is mediated by RNA, as their interaction was abrogated by RNase treatment. However, an MKRN3 missense mutation associated with CPP, p.C364F, within the E3 ubiquitin ligase domain, did not affect the RNA mediated interaction. Preliminary data from RNA co-IP, aiming to identify putative RNA targets, suggested that MKRN3 and IGF2BP1 bind to TAC3 mRNA. We further identified an increase in Nkb protein levels in the hypothalamus of Mkrn3 KO mice. We also showed that NKB is a substrate of MKRN3 E3 ubiquitin ligase activity in vitro by demonstrating increased ubiquitination of NKB in cells co-transfected with expression vectors encoding MKRN3 and NKB and treated with proteasome inhibitor. Additionally, MKRN3 overexpression resulted in degradation of NKB protein by western blot analysis, and alteration of NKB intracellular localization by immunofluorescence. These effects were impaired by MKRN3 missense mutations (p.C340G and p.C364F) in the E3 ubiquitin ligase motif, suggesting a pathophysiological mechanism of MKRN3 mutations in CPP. Conclusions We identified that MKRN3 interacts with PABPC1, PABPC4 and IGF2BP1 and targets NKB to degradation. We showed that NKB degradation was mediated by the MKRN3 E3 ubiquitin ligase domain, as mutations within this motif abrogated NKB degradation. However, this mutation did not affect MKRN3 RNA-mediated binding to IGF2BP1, highlighting that multiple domains of MKRN3 may contribute to its actions. Here, we propose a mechanism by which MKRN3, interacting with PABPCs and IGF2BP1 and targeting NKB for degradation, may act to inhibit the reproductive axis. Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

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Meader, Brooke N., Alessandro Albano, Hilal Sekizkardes, and Angela Delaney. "Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome." Journal of Clinical Endocrinology & Metabolism 105, no. 8 (June 1, 2020): 2732–39. http://dx.doi.org/10.1210/clinem/dgaa331.

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Abstract Context Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated. Objective To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP. Methods Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1. Results Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family. Conclusions We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.

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Macedo, Delanie B., Monica M. França, Luciana R. Montenegro, Marina Cunha-Silva, Danielle S. Bessa, Ana Paula Abreu, Ursula B. Kaiser, et al. "Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region." Neuroendocrinology 107, no. 2 (2018): 127–32. http://dx.doi.org/10.1159/000490059.

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Context: Loss-of-function mutations in the coding region of MKRN3, a maternally imprinted gene at chromosome 15q11.2, are a common cause of familial central precocious puberty (CPP). Whether MKRN3 alterations in regulatory regions can cause CPP has not been explored to date. We aimed to investigate potential pathogenic variants in the promoter region of MKRN3 in patients with idiopathic CPP. Patients/Methods: A cohort of 110 patients with idiopathic CPP was studied. Family history of precocious sexual development was present in 25%. Mutations in the coding region of MKRN3 were excluded in all patients. Genomic DNA was extracted from peripheral blood leukocytes, and 1,100 nucleotides (nt) of the 5′-regulatory region of MKRN3 were amplified and sequenced. Luciferase assays were performed in GT1–7 cells transiently transfected with plasmids containing mutated and wild-type MKRN3 promoter. Results: We identified a rare heterozygous 4-nt deletion (c.-150_-147delTCAG; –38 to –41 nt upstream to the transcription start site) in the proximal promoter region of MKRN3 in a girl with CPP. In silico analysis predicted that this deletion would lead to the loss of a binding site for a downstream responsive element antagonist modulator (DREAM), a potential transcription factor for MKRN3 and GNRH1 expression. Luciferase assays demonstrated a significant reduction of MKRN3 promoter activity in transfected cells with a c.-150_- 147delTCAG construct plasmid in both homozygous and heterozygous states when compared with cells transfected with the corresponding wild-type MKRN3 promoter region. Conclusion: A rare genetic alteration in the regulatory region of MKRN3 causes CPP.

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Atay, Enver, Suna Kılınç, Gozde Ulfer, Turkan Yigitbasi, Cagri Cakici, Murat Turan, Omer Ceran, and Zeynep Atay. "The role of makorin ring finger protein-3, kisspeptin, and neurokinin B in the physiology of minipuberty." Journal of Pediatric Endocrinology and Metabolism 34, no. 3 (January 8, 2021): 325–32. http://dx.doi.org/10.1515/jpem-2020-0331.

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Abstract Background There is no data regarding the interrelationships of circulating Makorin Ring Finger Protein-3 (MKRN3), Kisspeptin (KISS1), and Neurokinin B (NKB) concentrations during minipuberty in humans. Objective To determine temporal changes in circulating concentrations of MKRN3, KISS1, NKB, and gonadotropins and investigate interrelationships between them in healthy full-term (FT) and preterm (PT) infants during minipuberty period. Methods A prospective study of 6-month follow-up performed. Eighty-seven healthy newborns, 48 FT (19 boys/29 girls), and 39 PT (21 boys/18 girls) (gestational age 31–37 weeks), were included. Blood samples were taken at 7 days (D7), 2 months (M2), and 6 months (M6) of age. Serum MKRN3, KISS1, NKB, LH, FSH, total testosterone (TT), and estradiol (E2) concentrations were measured. Results Seventy infants completed the study. MKRN3, KISS1, and NKB concentrations were similar in FT girls and boys. PT boys and girls also had similar concentrations of MKRN3, KISS1, and NKB. FT babies had significantly higher NKB concentrations than PT babies at D7, M2, and M6. MKRN3 and KISS1 concentrations do not differ between FT and PT babies. A strong positive correlation was found between MKRN3 and KISS1 at each time point and in all groups. FSH, LH, TT/E2 concentrations decrease while those of MKRN3 and KISS1 have a trend to increase toward the end of minipuberty. No correlation was detected between gonadotropins and MKRN3, KISS1, NKB concentrations. Conclusion Strong positive correlation demonstrated between KISS1 and MKRN3 suggests that interrelationship between molecules controlling minipuberty is not similar to those at puberty.

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Ramos, Carolina de Oliveira, Delanie B. Macedo, Ana Pinheiro M. Canton, Marina Cunha-Silva, Sonir R. R. Antonini, Monica Freire Stecchini, Carlos Eduardo Seraphim, et al. "Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog." Neuroendocrinology 110, no. 7-8 (October 31, 2019): 705–13. http://dx.doi.org/10.1159/000504446.

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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.

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Grandone, Anna, Grazia Cirillo, Marcella Sasso, Gianluca Tornese, Caterina Luongo, Adalgisa Festa, Pierluigi Marzuillo, and Emanuele Miraglia del Giudice. "MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study." Hormone Research in Paediatrics 90, no. 3 (2018): 190–95. http://dx.doi.org/10.1159/000493134.

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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.

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Varimo, Tero, Leo Dunkel, Kirsi Vaaralahti, Päivi J. Miettinen, Matti Hero, and Taneli Raivio. "Circulating makorin ring finger protein 3 levels decline in boys before the clinical onset of puberty." European Journal of Endocrinology 174, no. 6 (June 2016): 785–90. http://dx.doi.org/10.1530/eje-15-1193.

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ObjectiveMakorin ring finger protein 3 (MKRN3) gene restrains the hypothalamic–pituitary–gonadal axis. In girls, peripheral levels of MKRN3 decline prior to the onset of puberty. We described longitudinal changes in serum MKRN3 levels in boys before and during puberty and assessed the effect of inhibition of estrogen biosynthesis on MKRN3 levels.DesignLongitudinal serum samples from a double-blind, randomized controlled study in 30 boys (age range: 9.1–14.2years) with idiopathic short stature who received placebo (Pl;n=14) or aromatase inhibitor letrozole (Lz; 2.5mg/day;n=16) for 2years.MethodsWe analyzed the relationships between serum MKRN3 and clinical and biochemical markers of puberty by using summary measures.ResultsSerum MKRN3 declined by 669±713 pg/mL per year (P<0.001). This change was biphasic, as the levels decreased during Tanner genital stage G1 (–2931±2750 pg/mL per year) and plateaued thereafter (–560±1510 pg/mL per year) (P<0.05). During G1, MKRN3 levels in Lz-treated subjects decreased slower than in Pl-treated boys (–782±3190 vs –2030±821 pg/mL per year,P<0.05). The decrease in serum MKRN3 levels in G1 was associated with increases in LH (r=–0.5,P<0.01), testosterone (r=–0.6,P<0.01), and inhibin B (r=–0.44,P<0.05) (n=26).ConclusionPeripheral MKRN3 levels in boys appear to serve as a readout of the diminishing central inhibition that controls the onset of puberty.

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Simon, Dominique, Ibrahima Ba, Nancy Mekhail, Emmanuel Ecosse, Anne Paulsen, Delphine Zenaty, Muriel Houang, et al. "Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty." European Journal of Endocrinology 174, no. 1 (January 2016): 1–8. http://dx.doi.org/10.1530/eje-15-0488.

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Context and objectiveIdiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic–pituitary–gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations.DesignAn observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients.ResultsMKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4–6.0) vs 7.0 years (6.0–7.0), P=0.01).ConclusionsMKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

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Li, Chuanyin, Tianting Han, Qingrun Li, Menghuan Zhang, Rong Guo, Yun Yang, Wenli Lu, et al. "MKRN3-mediated ubiquitination of Poly(A)-binding proteins modulates the stability and translation of GNRH1 mRNA in mammalian puberty." Nucleic Acids Research 49, no. 7 (March 21, 2021): 3796–813. http://dx.doi.org/10.1093/nar/gkab155.

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Abstract The family of Poly(A)-binding proteins (PABPs) regulates the stability and translation of messenger RNAs (mRNAs). Here we reported that the three members of PABPs, including PABPC1, PABPC3 and PABPC4, were identified as novel substrates for MKRN3, whose deletion or loss-of-function mutations were genetically associated with human central precocious puberty (CPP). MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA, which led to shortened poly(A) tail-length of GNRH1 mRNA and compromised the formation of translation initiation complex (TIC). Recently, we have shown that MKRN3 epigenetically regulates the transcription of GNRH1 through conjugating poly-Ub chains onto methyl-DNA bind protein 3 (MBD3). Therefore, MKRN3-mediated ubiquitin signalling could control both transcriptional and post-transcriptional switches of mammalian puberty initiation. While identifying MKRN3 as a novel tissue-specific translational regulator, our work also provided new mechanistic insights into the etiology of MKRN3 dysfunction-associated human CPP.

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Macedo, Delanie B., Ana Paula Abreu, Ana Claudia S. Reis, Luciana R. Montenegro, Andrew Dauber, Daiane Beneduzzi, Priscilla Cukier, et al. "Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3." Journal of Clinical Endocrinology & Metabolism 99, no. 6 (June 1, 2014): E1097—E1103. http://dx.doi.org/10.1210/jc.2013-3126.

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Context: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.

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Carroll, Rona, Ursula Kaiser, Han Kyeol Kim, Kali McKnight, Lydie Naule, Sidney Pereira, Miguel Sena-Esteves, and Stephanie Roberts. "OR18-1 The Impact of Makorin Ring Finger Protein 3 (MKRN3) Overexpression in the Arcuate Nucleus of Postpubertal Female Mice on the HPG Axis." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A616—A617. http://dx.doi.org/10.1210/jendso/bvac150.1278.

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Abstract Background and Objective Makorin Ring Finger Protein 3 (MKRN3), an inhibitor of the KISS1 and TAC3 promoters in the hypothalamic arcuate nucleus (ARC), is an important player in age of menarche and etiology of central precocious puberty. However, its potential role in delayed puberty and/or hypogonadism is not defined. Mkrn3 expression in the ARC declines prior to the onset of puberty and remains low in adulthood, supporting its role as an inhibitor of pubertal onset. Neonatal hypothalamic overexpression of Mkrn3 leads to delayed puberty in female mice; this study aimed to explore the effects of MKRN3 overexpression in the postpubertal mouse. We hypothesized that MKRN3 overexpression in the ARC of postpubertal female mice would result in suppression of the HPG axis, manifested as hypogonadotropic hypogonadism. Methods and Results Adult female C57BL/6 mice were stereotaxically injected into the ARC with a recombinant adeno-associated virus (rAAV-Mkrn3-IRES-EGFP;n=12) to overexpress Mkrn3, or with a control virus (rAAV-EGFP;n=9). Daily vaginal smears collected six weeks post-injection showed that rAAV-Mkrn3 injected mice spent significantly more time (62.7%) in diestrus compared to controls (41.3%;P<0.01). Mean body weight did not statistically differ between groups. Eight weeks after viral injection, gonad-intact females underwent stimulation tests while in diestrus. Tail vein blood samples were collected at baseline and 20, 40 and 60 minutes after stimulation. In response to the NK3R agonist, senktide, evaluated at two doses (5 nmol and 10 nmol ip, respectively), Mkrn3-overexpressing mice had a reduced peak (i.e., T20) LH response compared to controls (P<0.001 for both dosing paradigms). In contrast, in response to kisspeptin-10 (1 nmol ip), mice responded with similar peak serum LH levels. Subsequently, tests were repeated seven days after ovariectomy and estradiol capsule replacement (OVX+E2). Peak LH levels (T20) were again significantly lower in response to senktide (5 nmol ip) in the rAAV-Mkrn3 injected females (P<0.001). Peak serum LH levels (T20) were not different in response to kisspeptin-10 (1 nmol) or GnRH (1.25 ng/g body weight). Additionally, there were no significant differences in serum LH levels between groups 7 days after OVX or OVX + E2. Conclusions In this novel mouse model, developed to investigate the mechanism of action of MKRN3, an important neuroendocrine controller of puberty initiation, these findings suggest that MKRN3 can exert inhibitory effects on the reproductive axis in female mice beyond the juvenile period. In these mice, response to kisspeptin and GnRH was preserved but the response to senktide was blunted. These findings suggest that Mkrn3 may act in ARC kisspeptin neurons to inhibit kisspeptin synthesis or secretion and/or potentially the action of neurokinin B via its receptor. Modulation of MKRN3 expression may be a future therapeutic target for reproductive disorders. Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.

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Li, Junliang, Weina Chen, Dongjie Li, Shukai Gu, Xiaoqian Liu, Yanqiu Dong, Lanjie Jin, Cui Zhang, and Shijie Li. "Conservation of Imprinting and Methylation of MKRN3, MAGEL2 and NDN Genes in Cattle." Animals 11, no. 7 (July 2, 2021): 1985. http://dx.doi.org/10.3390/ani11071985.

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Genomic imprinting is the epigenetic mechanism of transcriptional regulation that involves differential DNA methylation modification. Comparative analysis of imprinted genes between species can help us to investigate the biological significance and regulatory mechanisms of genomic imprinting. MKRN3, MAGEL2 and NDN are three maternally imprinted genes identified in the human PWS/AS imprinted locus. This study aimed to assess the allelic expression of MKRN3, MAGEL2 and NDN and to examine the differentially methylated regions (DMRs) of bovine PWS/AS imprinted domains. An expressed single-nucleotide polymorphism (SNP)-based approach was used to investigate the allelic expression of MKRN3, MAGEL2 and NDN genes in bovine adult tissues and placenta. Consistent with the expression in humans and mice, we found that the MKRN3, MAGEL2 and NDN genes exhibit monoallelic expression in bovine somatic tissues and the paternal allele expressed in the bovine placenta. Three DMRs, PWS-IC, MKRN3 and NDN DMR, were identified in the bovine PWS/AS imprinted region by analysis of the DNA methylation status in bovine tissues using the bisulfite sequencing method and were located in the promoter and exon 1 of the SNRPN gene, NDN promoter and 5’ untranslated region (5’UTR) of MKRN3 gene, respectively. The PWS-IC DMR is a primary DMR inherited from the male or female gamete, but NDN and MKRN3 DMR are secondary DMRs that occurred after fertilization by examining the methylation status in gametes.

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Grandone, Anna, Carlo Capristo, Grazia Cirillo, Marcella Sasso, Giuseppina Rosaria Umano, Michela Mariani, Emanuele Miraglia Del Giudice, and Laura Perrone. "Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty." Hormone Research in Paediatrics 88, no. 3-4 (2017): 194–200. http://dx.doi.org/10.1159/000477441.

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Background: Mutations in the imprinted gene MKRN3 have been described as a common genetic cause of idiopathic central precocious puberty (CPP), in particular in familial cases. However, the exact prevalence of mutations is unknown. Single nucleotide polymorphisms in 2 other imprinted genes, DLK1 and KCNK9, have been associated with age at menarche. We investigated the prevalence of mutations in MKRN3, DLK1, and KCNK9 genes in a cohort of girls with idiopathic CPP. Methods: MKRN3, DLK1, and KCNK9 coding regions were sequenced in 60 girls with idiopathic CPP (familial in 23 cases). Results: Three mutations, including a new one, in MKRN3 were found in 2 familial cases (c.1229G>A; p.Cys410Ter and c.477_485del; p.Pro160Cysfs*14) (8.7%) and in 1 sporadic case (c.982C>T; p.Arg328Cys) (2.8%). We did not find rare variants in DLK1 and KCNK9 genes. Conclusions: (1) The prevalence of MKRN3 mutations in our cohort was similar to that reported in the literature in sporadic cases but lower than previously described in familial ones. This could be due to different inheritance patterns of families studied; (2) we expanded the phenotype of MKRN3 defects describing 3 more patients with MKRN3 mutations; and (3) point mutations in DLK1 and KCNK9 at least do not seem to be a common cause of CPP in girls.

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Li, Chuanyin, Wenli Lu, Liguang Yang, Zhengwei Li, Xiaoyi Zhou, Rong Guo, Junqi Wang, et al. "MKRN3 regulates the epigenetic switch of mammalian puberty via ubiquitination of MBD3." National Science Review 7, no. 3 (February 14, 2020): 671–85. http://dx.doi.org/10.1093/nsr/nwaa023.

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Abstract 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.

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Settas, Nikolaos, Catherine Dacou-Voutetakis, Maria Karantza, Christina Kanaka-Gantenbein, George P. Chrousos, and Antonis Voutetakis. "Central Precocious Puberty in a Girl and Early Puberty in Her Brother Caused by a Novel Mutation in the MKRN3 Gene." Journal of Clinical Endocrinology & Metabolism 99, no. 4 (April 1, 2014): E647—E651. http://dx.doi.org/10.1210/jc.2013-4084.

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Context: Central precocious puberty (CPP), defined as the development of secondary sex characteristics prior to age 8 years in girls and 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal axis. Mutations in the imprinted gene MKRN3 have been recently implicated in familial cases of CPP. Objective: The objective of the study was to uncover the genetic cause of CPP in a family with two affected siblings. Design and participants: The entire coding region of the paternally expressed MKRN3 gene was sequenced in two siblings, a girl with CPP and her brother with early puberty, their parents, and their grandparents. Results: A novel heterozygous missense variant in the MKRN3 gene (p.C340G) was detected in the two affected siblings, their unaffected father, and the paternal grandmother. As expected, the mutated allele followed an imprinted mode of inheritance within the affected family. In silico analysis predicts the mutation as possibly damaging in all five software packages used. Furthermore, structural alignment of the ab initio native and mutant MKRN3 models predicts that the p.C340G mutation leads to significant structural perturbations in the 3-dimensional structure of the C3HC4 really interesting new gene motif of the protein, further emphasizing the functional implications of the novel MKRN3 alteration. Conclusions: We report a novel MKRN3 mutation (p.C340G) in a girl with CPP and her brother with early puberty. MKRN3 alterations should be suspected in all cases with familial CPP or early puberty, especially if male patients are also involved or the precocious puberty trend does not follow the usually observed mother-to-daughter inheritance.

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Niemitz, Emily. "MKRN3 and pubertal timing." Nature Genetics 45, no. 7 (June 26, 2013): 722. http://dx.doi.org/10.1038/ng.2690.

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Yaqub, Farhat. "MKRN3 and central precocious puberty." Lancet Diabetes & Endocrinology 1 (August 2013): s15. http://dx.doi.org/10.1016/s2213-8587(13)70041-x.

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Montenegro, Luciana, José I. Labarta, Maira Piovesan, Ana P. M. Canton, Raquel Corripio, Leandro Soriano-Guillén, Lourdes Travieso-Suárez, et al. "Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian–Spanish Study." Journal of Clinical Endocrinology & Metabolism 105, no. 10 (July 17, 2020): 3165–72. http://dx.doi.org/10.1210/clinem/dgaa461.

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Abstract Background Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. Patients A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. Results Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in 2 girls with CPP. However, both had normal DLK1 serum levels. Conclusion Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.

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Zubkova, N. A., A. A. Kolodkina, N. A. Makretskaya, P. L. Okorokov, T. V. Pogoda, E. V. Vasiliev, V. M. Petrov, and A. N. Tiulpakov. "Clinical and molecular genetic features of 3 family cases of the central precocious puberty, due to MKRN3 gene defects." Problems of Endocrinology 67, no. 3 (July 22, 2021): 55–61. http://dx.doi.org/10.14341/probl12745.

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Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.

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Sazhenova, E. A., S. A. Vasilyev, L. V. Rychkova, E. E. Khramova, and I. N. Lebedev. "Genetics and Epigenetics of Precocious Puberty." Генетика 59, no. 12 (December 1, 2023): 1360–71. http://dx.doi.org/10.31857/s001667582312010x.

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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 non-coding 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 literature data on the molecular genetic and epigenetic mechanisms of the formation of СPP.

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Argente, Jesús, Vinicius Brito, Aline Guimaraes, Ana Claudia Latronico, Andrea Leal, Berenice Mendonça, Luciana Montenegro, et al. "OR18-2 Clinical, Hormonal and Genetic Characterization of Familial Central Precocious Puberty." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A617. http://dx.doi.org/10.1210/jendso/bvac150.1279.

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Abstract Context: Familial central precocious puberty (CPP) is a prevalent form (about 27.5%) of precocious puberty. Loss-of-function mutations in two maternally imprinted genes, MKRN3 and DLK1, were identified in families with CPP showing dominant autosomal inheritance with paternal transmission. Maternally transmitted CPP was previously demonstrated in up to 60% of families using pedigree analysis, however, no definitive genetic abnormality has been identified so far. Objectives To estimate the prevalence of familial cases in a multiethnic cohort with CPP. To characterize the genetic basis and the mode of inheritance of the affected families. To compare clinical and hormonal features of patients with familial CPP due to different modes of transmission. Patients and Methods Clinical and hormonal data were obtained from medical registries of 495 patients with CPP and no brain MRI alterations. Familial CPP was defined as the presence of one or more close relatives with CPP or precocious menarche (≤9 yr). Sanger sequencing of MKRN3 and DLK1 was performed in 427 index cases. Targeted gene panel sequencing was performed in 79 cases, while whole exome sequencing was performed in 101 cases from 36 families Results Among 495 index cases, 159 had familial CPP (31%). The mode of transmission of CPP was identified as paternal in 58 (35%), maternal in 59 (38%), indeterminate in 34 (22%), and both maternal and paternal transmission in 8 (5%). Most families with paternal or maternal transmission had 2 generations known to be affected (51 and 77%, respectively). Notably, 67% of index cases with maternally transmitted CPP had their mother affected. In girls with CPP, the median age of thelarche was 6.5 yr in the paternally transmitted group, 6.9 yr in the maternally transmitted group, and 7.3 yr in the indeterminate group (p= 0.547). Median bone age advancement was 2.1, 2.3 and 1.2 yr, respectively (p= 0.013). Basal LH levels were higher in girls with paternally transmitted CPP (p= 0.047). Among those with paternally transmitted CPP, MKRN3 and DLK1 mutations were identified in, respectively, 63.8% and 10.3% of the families. Conclusions A significant prevalence (31%) of familial CPP was demonstrated in a multiethnic cohort. Maternally transmitted CPP represented the most frequent form of familial CPP (38%). MKRN3 loss-of-function mutations were responsible for most paternally transmitted CPP cases (63.8%), followed by DLK1 loss-of-function mutations (10.3%). Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.

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de Vries, L., G. Gat-Yablonski, N. Dror, A. Singer, and M. Phillip. "A novel MKRN3 missense mutation causing familial precocious puberty." Human Reproduction 29, no. 12 (October 14, 2014): 2838–43. http://dx.doi.org/10.1093/humrep/deu256.

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Dimitrova-Mladenova, Mihaela S., Elisaveta M. Stefanova, Maria Glushkova, Albena P. Todorova, Tihomir Todorov, Maia M. Konstantinova, Krasimira Kazakova, and Radka S. Tincheva. "Males with Paternally Inherited MKRN3 Mutations May Be Asymptomatic." Journal of Pediatrics 179 (December 2016): 263–65. http://dx.doi.org/10.1016/j.jpeds.2016.08.065.

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Busch, Alexander S., Casper P. Hagen, Kristian Almstrup, and Anders Juul. "Circulating MKRN3 Levels Decline During Puberty in Healthy Boys." Journal of Clinical Endocrinology & Metabolism 101, no. 6 (June 2016): 2588–93. http://dx.doi.org/10.1210/jc.2016-1488.

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Toutoudaki, Konstantina, George Paltoglou, Dimitrios T. Papadimitriou, Anna Eleftheriades, Ermioni Tsarna, and Panagiotis Christopoulos. "The Role of SNPs in the Pathogenesis of Idiopathic Central Precocious Puberty in Girls." Children 10, no. 3 (February 25, 2023): 450. http://dx.doi.org/10.3390/children10030450.

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The initiation of puberty is a crucial timepoint of development, with its disruptions being associated with multiple physical and psychological complications. Idiopathic Central Precocious Puberty (iCPP) has been correlated with Single-Nucleotide Polymorphisms (SNPs) of certain genes that are implicated in various steps of the process of pubertal onset. The aim of this review was to gather current knowledge on SNPs of genes associated with iCPP. We searched articles published on the PubMed, EMBASE and Google Scholar platforms and gathered current literature. KISS1, KISS1R, PLCB1, PRKCA, ITPR1, MKRN3, HPG axis genes, NPVF/NPFFR1, DLK1, KCNK9Q, LIN28B, PROK2R, IGF-1, IGF2, IGF-1R, IGF-2R, IGFBP-3, insulin, IRS-1, LEP/LEPR, PPARγ2, TAC3, TACR3, Estrogen receptors, CYP3A4 and CYP19A1 were studied for implication in the development of precocious puberty. SNPs discovered in genes KISS1, KISS1R, PLCB1, MKRN3, NPVF, LIN28B, PROK2R, IRS-1 TAC3, and CYP3A4 were significantly correlated with CPP, triggering or protecting from CPP. Haplotype (TTTA)13 in CYP19A1 was a significant contributor to CPP. Further investigation of the mechanisms implicated in the pathogenesis of CPP is required to broaden the understanding of these genes’ roles in CPP and possibly initiate targeted therapies.

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Christoforidis, Athanasios, Nicos Skordis, Pavlos Fanis, Meropi Dimitriadou, Maria Sevastidou, Marie M. Phelan, Vassos Neocleous, and Leonidas A. Phylactou. "A novel MKRN3 nonsense mutation causing familial central precocious puberty." Endocrine 56, no. 2 (January 28, 2017): 446–49. http://dx.doi.org/10.1007/s12020-017-1232-6.

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Roberts, Stephanie A., and Ursula B. Kaiser. "GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes." European Journal of Endocrinology 183, no. 4 (October 2020): R107—R117. http://dx.doi.org/10.1530/eje-20-0103.

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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.

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Aycan, Zehra, Şenay Savaş-Erdeve, Semra Çetinkaya, Erdal Kurnaz, Melikşah Keskin, Nursel Muratoğlu Şahin, Elvan Bayramoğlu, and Gülay Ceylaner. "Investigation of MKRN3 Mutation in Patients with Familial Central Precocious Puberty." Journal of Clinical Research in Pediatric Endocrinology 10, no. 3 (July 31, 2018): 223–29. http://dx.doi.org/10.4274/jcrpe.5506.

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Abreu, Ana Paula, Andrew Dauber, Delanie B. Macedo, Sekoni D. Noel, Vinicius N. Brito, John C. Gill, Priscilla Cukier, et al. "Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3." New England Journal of Medicine 368, no. 26 (June 27, 2013): 2467–75. http://dx.doi.org/10.1056/nejmoa1302160.

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Schreiner, Felix, Bettina Gohlke, Michaela Hamm, Eckhard Korsch, and Joachim Woelfle. "MKRN3 Mutations in Familial Central Precocious Puberty." Hormone Research in Paediatrics 82, no. 2 (2014): 122–26. http://dx.doi.org/10.1159/000362815.

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Eugster, E. "Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3." Yearbook of Endocrinology 2014 (2014): 268–69. https://doi.org/10.1016/j.yend.2013.06.003.

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Lee, H., H. S. Jin, Y. Shim, H. Jeong, E. Kwon, V. Choi, M. C. Kim, I. S. Chung, S. Y. Jeong, and J. Hwang. "Low Frequency of MKRN3 Mutations in Central Precocious Puberty Among Korean Girls." Hormone and Metabolic Research 48, no. 02 (May 4, 2015): 118–22. http://dx.doi.org/10.1055/s-0035-1548938.

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Valadares, Luciana Pinto, Cinthia Gabriel Meireles, Isabela Porto De Toledo, Renata Santarem de Oliveira, Luiz Cláudio Gonçalves de Castro, Ana Paula Abreu, Rona S. Carroll, et al. "MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis." Journal of the Endocrine Society 3, no. 5 (March 25, 2019): 979–95. http://dx.doi.org/10.1210/js.2019-00041.

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Dauber, Andrew, Marina Cunha-Silva, Delanie B. Macedo, Vinicius N. Brito, Ana Paula Abreu, Stephanie A. Roberts, Luciana R. Montenegro, et al. "Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty." Journal of Clinical Endocrinology & Metabolism 102, no. 5 (January 27, 2017): 1557–67. http://dx.doi.org/10.1210/jc.2016-3677.

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Анотація:

Abstract Context: Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3. Objective: To identify the genetic etiology of CPP in a large multigenerational family. Design: Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro. Setting: Endocrine clinic of an academic medical center. Patients: Patients with familial CPP were studied. Results: A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5′ untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines. Conclusion: We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.

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Simsek, Enver, Meliha Demiral, Serdar Ceylaner, and Birgul Kırel. "Two Frameshift Mutations in MKRN3 in Turkish Patients with Familial Central Precocious Puberty." Hormone Research in Paediatrics 87, no. 6 (November 1, 2016): 405–11. http://dx.doi.org/10.1159/000450923.

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39

Liu, Huifang, Xiangxin Kong, and Fengling Chen. "Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation." Oncotarget 8, no. 49 (July 18, 2017): 85102–9. http://dx.doi.org/10.18632/oncotarget.19347.

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Abreu, Ana Paula, Delanie B. Macedo, Vinicius N. Brito, Ursula B. Kaiser, and Ana Claudia Latronico. "A new pathway in the control of the initiation of puberty: the MKRN3 gene." Journal of Molecular Endocrinology 54, no. 3 (June 2015): R131—R139. http://dx.doi.org/10.1530/jme-14-0315.

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Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The role ofMKRN3, an imprinted gene located in the Prader–Willi syndrome critical region (chromosome 15q11–13), in pubertal initiation was first described in 2013 after the identification of deleteriousMKRN3mutations in five families with central precocious puberty (CPP) using whole-exome sequencing analysis. Since then, additional loss-of-function mutations ofMKRN3have been associated with the inherited premature sexual development phenotype in girls and boys from different ethnic groups. In all of these families, segregation analysis clearly demonstrated autosomal dominant inheritance with complete penetrance, but with exclusive paternal transmission, consistent with the monoallelic expression ofMKRN3(a maternally imprinted gene). Interestingly, the hypothalamicMkrn3mRNA expression pattern in mice correlated with a putative inhibitory input on puberty initiation. Indeed, the initiation of puberty depends on a decrease in factors that inhibit the release of GnRH combined with an increase in stimulatory factors. These recent human and animal findings suggest thatMKRN3plays an inhibitory role in the reproductive axis to represent a new pathway in pubertal regulation.

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Heras, Violeta, Susana Sangiao-Alvarellos, Maria Manfredi-Lozano, María J. Sanchez-Tapia, Francisco Ruiz-Pino, Juan Roa, Maribel Lara-Chica, et al. "Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3." PLOS Biology 17, no. 11 (November 7, 2019): e3000532. http://dx.doi.org/10.1371/journal.pbio.3000532.

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42

Brito, Vinicius Nahime, and Ana Claudia Latronico. "Underdiagnosis of central precocious puberty in boys with loss-of-function mutations of MKRN3." Journal of Pediatrics 183 (April 2017): 202–3. http://dx.doi.org/10.1016/j.jpeds.2016.12.023.

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43

Wang, Tongtong, Wenqiang Liu, Changfa Wang, Xuelian Ma, Muhammad Faheem Akhtar, Yubao Li, and Liangliang Li. "MRKNs: Gene, Functions, and Role in Disease and Infection." Frontiers in Oncology 12 (April 8, 2022). http://dx.doi.org/10.3389/fonc.2022.862206.

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The makorin RING finger protein (MKRN) gene family encodes proteins (makorins) with a characteristic array of zinc-finger motifs present in a wide array from invertebrates to vertebrates. MKRNs (MKRN1, MKRN2, MKRN3, MKRN4) as RING finger E3 ligases that mediate substrate degradation are related with conserved RING finger domains that control multiple cellular components via the ubiquitin-proteasome system (UPS), including p53, p21, FADD, PTEN, p65, Nptx1, GLK, and some viral or bacterial proteins. MKRNs also served as diverse roles in disease, like MKRN1 in transcription regulation, metabolic disorders, and tumors; MKRN2 in testis physiology, neurogenesis, apoptosis, and mutation of MKRN2 regulation signals transduction, inflammatory responses, melanoma, and neuroblastoma; MKRN3 in central precocious puberty (CPP) therapy; and MKRN4 firstly reported as a novel E3 ligase instead of a pseudogene to contribute to systemic lupus erythematosus (SLE). Here, we systematically review advances in the gene’s expression, function, and role of MKRNs orthologs in disease and pathogens infection. Further, MKRNs can be considered targets for the host’s innate intracellular antiviral defenses and disease therapy.

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44

Yang, Yun, Yanyan Luo, Shuting Huang, Yonghui Tao, Chuanyin Li, and Chengcheng Wang. "MKRN1/2 serve as tumor suppressors in renal clear cell carcinoma by regulating the expression of p53." Cancer Biomarkers, March 9, 2023, 1–12. http://dx.doi.org/10.3233/cbm-210559.

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BACKGROUND: Kidney renal clear cell carcinoma (KIRC) belongs to renal cell carcinoma which is a very aggressive malignant tumor with poor prognosis and high mortality. The MKRN family includes three members MKRN1, MKRN2 and MKRN3, which are closely related to cancers, and have been involved in many studies. OBJECTIVE: This study aimed to explore the roles of MKRN family in KIRC. METHODS: The expression of MKRNs was analyzed using the UALCAN database, prognostic analysis was performed with the GEPIA2 and Kaplan-Meier Plotter database, and correlation analysis was assessed by GEPIA2. The CCK-8 and colony formation assay were performed to detect cell proliferation, wound healing assays were performed to detect cell migration, cell cycles were detected by flow cytometry analysis, GST pull-down and co-immunoprecipitation assays were performed to detect the interaction of proteins, and the expression of MKRNs, p53 and other proteins were detect by immunoblotting analysis or quantitative PCR (qPCR). RESULTS: MKRN1 and MKRN2 were lowly expressed in KIRC samples compared to the corresponding normal tissues, and KIRC patients with high levels of MKRN1 and MKRN2 showed higher overall survival (OS) and disease free survival (DFS) rates. The overexpression of MKRN1 and MKRN2 inhibited the proliferation of human KIRC cells by arresting the cell cycles, but shows little effect on cells migration. The expression of MKRN1 and MKRN2 are correlated, and MKRN1 directly interacts with MKRN2. Moreover, both MKRN1 and MKRN2 were closely correlated with the expression of TP53 in KIRC tumor, and promoted the expression of p53 both at protein and mRNA levels. CONCLUSIONS: Our study suggests that MKRN1 and MKRN2 serve as tumor suppressors in KIRC, and act as promising therapeutic targets for KIRC treatment.

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Li, Ke, Xufen Zheng, Hua Tang, Yuan-Sheng Zang, Chunling Zeng, Xiaoxiao Liu, Yanying Shen, et al. "E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non–small cell lung cancer." Journal of Experimental Medicine 218, no. 8 (June 18, 2021). http://dx.doi.org/10.1084/jem.20210151.

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Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non–small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell–specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry–based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor.

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46

Zhang, Shuiting, Chao Liu, Guo Li, Yong Liu, Xingwei Wang, and Yuanzheng Qiu. "Elevated expression of MKRN3 in squamous cell carcinoma of the head and neck and its clinical significance." Cancer Cell International 21, no. 1 (October 24, 2021). http://dx.doi.org/10.1186/s12935-021-02271-6.

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Abstract Background Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common types of cancer that cause a substantial number of cancer-related deaths. Our previous study has revealed that makorin ring finger protein 3 (MKRN3) may act as a key regulator of the SCCHN tumorigenesis; however, its specific role in SCCHN progression has not been reported. Methods The Cancer Genome Atlas (TCGA) data analysis and quantitative polymerase chain reaction (qPCR) were used to quantify the MKRN3 mRNA expression levels in SCCHN; immunohistochemical staining or immunoblotting analyses were performed to detect MKRN3 protein expression. Kaplan–Meier plotter was used to assess the prognostic values of MKRN3 in terms of overall survival and disease-free survival. The expression differences based on various clinicopathological features were evaluated using subgroup analysis and forest map analysis. The regulatory mechanism of MKRN3 was further investigated using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Subsequently, STRING was used to perform a co-expression and enrichment analysis for MKRN3. Homologous modeling, molecular docking, and western blot analyses were performed to investigate the relationship between MKRN3 and its potential target gene P53. Results MKRN3 was ectopically expressed between cancerous and noncancerous SCCHN tissues, and its expression level was tightly associated with high T classifications as well as advanced clinical stages. qPCR analysis revealed that MKRN3 was upregulated in the SCCHN cell line. Moreover, Kaplan–Meier and Cox regression analyses indicated that SCCHN patients with high MKRN3 expression had poorer prognosis and that MKRN3 was a potential prognostic marker for SCCHN. Using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we determined that MKRN3 may be involved in the regulation of synthesis and metabolism and cell growth, death and motility, as well as cancer pathways associated with SCCHN progression. Mechanism investigation further revealed that P53, a potential target of MKRN3, may be involved in the SCCHN tumorigenesis mediated by MKRN3. Conclusions We performed a comprehensive evaluation of the clinical significance of MKRN3 and explored its underlying mechanisms. We concluded that MKRN3 represents a valuable predictive biomarker and potential therapeutic target in SCCHN.

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Pereira, Sidney A., Fernanda C. B. Oliveira, Lydie Naulé, Carine Royer, Francisco A. R. Neves, Ana Paula Abreu, Rona S. Carroll, Ursula B. Kaiser, Michella S. Coelho, and Adriana Lofrano-Porto. "Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG." Endocrinology 164, no. 9 (August 1, 2023). http://dx.doi.org/10.1210/endocr/bqad123.

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Abstract Studies in humans and mice support a role for Makorin RING finger protein 3 (MKRN3) as an inhibitor of gonadotropin-releasing hormone (GnRH) secretion prepubertally, and its loss of function is the most common genetic cause of central precocious puberty in humans. Studies have shown that the gonads can synthesize neuropeptides and express MKRN3/Mkrn3 mRNA. Therefore, we aimed to investigate the spatiotemporal expression pattern of Mkrn3 in gonads during sexual development, and its potential regulation in the functional testicular compartments by gonadotropins. Mkrn3 mRNA was detected in testes and ovaries of wild-type mice at all ages evaluated, with a sexually dimorphic expression pattern between male and female gonads. Mkrn3 expression was highest peripubertally in the testes, whereas it was lower peripubertally than prepubertally in the ovaries. Mkrn3 is expressed primarily in the interstitial compartment of the testes but was also detected at low levels in the seminiferous tubules. In vitro studies demonstrated that Mkrn3 mRNA levels increased in human chorionic gonadotropin (hCG)–treated Leydig cell primary cultures. Acute administration of a GnRH agonist in adult mice increased Mkrn3 expression in testes, whereas inhibition of the hypothalamic–pituitary–gonadal axis by chronic administration of GnRH agonist had the opposite effect. Finally, we found that hCG increased Mkrn3 mRNA levels in a dose-dependent manner. Taken together, our developmental expression analyses, in vitro and in vivo studies show that Mkrn3 is expressed in the testes, predominantly in the interstitial compartment, and that Mkrn3 expression increases after puberty and is responsive to luteinizing hormone/hCG stimulation.

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Chen, Bangzhu, Xing Ye, Lihao Chen, Tianping Liu, Guiling Li, Chula Sa, Juan Li, Ke Liu, Weiwang Gu, and Gang Wang. "A novel model of central precocious puberty disease: Paternal MKRN3 gene–modified rabbit." Animal Models and Experimental Medicine, January 24, 2025. https://doi.org/10.1002/ame2.12544.

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AbstractBackgroundMakorin ring finger protein 3 gene (MKRN3) gene mutation is the most common genetic cause of central precocious puberty (CPP) in children. Due to the lack of ideal MKRN3‐modified animal model (MKRN3‐modified mice enter puberty only 4–5 days earlier than normal mice), the related research is limited.MethodsTherefore, the MKRN3‐modified rabbit was developed using CRISPR (clustered regularly interspaced short palindromic repeats) gene editing technology. The genotype identification and phenotype evaluation of MKRN3‐modified rabbits were carried out.ResultsThe first estrus of MKRN3‐modified female rabbits was observed ~27 days earlier than that of wild‐type female rabbits, with a typical CPP phenotype. This study found increased gonadotropin releasing hormone (GnRH) and decreased gonadotropin inhibiting hormone (GnIH) in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation. Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation, it found some differentially expressed genes and potential pathways through transcriptome sequencing.ConclusionsThis study established a novel CPP model: paternal MKRN3 gene‐modified rabbit. It is hoped that the establishment of this model will help researchers better understand, treat, and prevent CPP in the future.

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Roberts, S. A., A. Fontes, S. Blau, M. Magnuson, K. M. McKnight, M. Sena-Esteves, R. S. Carroll, and U. B. Kaiser. "7381 Overexpression of Makorin Ring Finger Protein 3 in the Arcuate Nucleus of Postpubertal Female Mice Impacts Neurokinin B and Kisspeptin Co-Expressing Neurons." Journal of the Endocrine Society 8, Supplement_1 (October 2024). http://dx.doi.org/10.1210/jendso/bvae163.1496.

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Abstract Disclosure: S.A. Roberts: None. A. Fontes: None. S. Blau: None. M. Magnuson: None. K.M. McKnight: None. M. Sena-Esteves: None. R.S. Carroll: None. U.B. Kaiser: None. Background: Makorin ring finger protein 3 (MKRN3), an upstream inhibitor of GnRH release, is an important regulator of the age of menarche. Loss-of-function mutations in MKRN3 are the most common genetic etiology of central precocious puberty. However, its potential role in delayed puberty or hypogonadism is not well defined. In mice, expression of Mkrn3 in the hypothalamic arcuate nucleus (ARC), where kisspeptin, neurokinin B and dynorphin (KNDy) co-expressing neurons are located, is high early in life and declines before pubertal onset. Neonatal hypothalamic overexpression of Mkrn3 leads to delayed puberty in female mice and decreased neurokinin B (NKB) and kisspeptin protein levels in the ARC peripubertally. Conversely, Mkrn3-deficient peripubertal mice exhibit increased NKB protein levels in the ARC. We hypothesized that Mkrn3 overexpression in the ARC of postpubertal female mice would result in suppression of the HPG axis, manifested as hypogonadotropic hypogonadism. Methods and Results: Twelve week old adult wild type female mice were injected stereotaxically into the ARC with a novel adeno-associated virus overexpressing Mkrn3 (AAV-Mkrn3-IRES-EGFP; denoted AAV-Mkrn3) or a control virus (AAV-EGFP). Mean body weight did not differ between groups post-injection. AAV-Mkrn3 injected mice spent significantly more time (62.7%) in diestrus three to six weeks post-injection compared to controls (41.3%; P<0.01). Eight weeks post-injection, gonad-intact females were injected with an NKB receptor (NK3R) agonist, senktide (5 nmol or 10 nmol ip). AAV-Mkrn3 mice had a decreased peak LH response twenty minutes post-injection, compared to controls (P<0.001) at both doses. Peak LH levels were also reduced in response to senktide (5 nmol ip) in ovariectomized and estradiol capsule replaced (OVX+E2) AAV-Mkrn3 injected females, compared to controls (P< 0.001). In contrast, in both gonad-intact and OVX+E2 female mice, kisspeptin-10 (1 nmol ip) resulted in similar peak serum LH levels in AAV-Mkrn3 injected mice compared to controls. Immunohistochemistry in the ARC of intact and OVX+E2 AAV-Mkrn3 injected females showed significantly decreased NKB protein expression in AAV-Mkrn3 mice compared to controls. In response to OVX, serum LH levels increased similarly between AAV-Mkrn3 and control-injected mice. LH pulsatility in OVX females, assessed over 3 hours, showed that mean basal LH levels, number of pulses, pulse amplitude and area under the curve did not differ significantly between groups. Conclusions: These findings indicate that MKRN3 can exert inhibitory effects on the reproductive axis in female mice beyond the juvenile period, which has implications as a potential therapeutic target. The blunted response to senktide, and decreased NKB protein levels in the setting of Mkrn3 overexpression, further supports the impact of Mkrn3 on the neuropeptides and/or receptors of KNDy neurons. Presentation: 6/2/2024

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Seraphim, Carlos Eduardo, Ana Pinheiro Machado Canton, Luciana Ribeiro Montenegro, Maiara Ribeiro Piovesan, Tabata Mariz Bohlen, Renata Frazao, Delanie Bulcão Macedo, et al. "SUN-085 Clinical and Hormonal Features of 37 Families with Central Precocious Puberty Due to MKRN3 Loss-Of -Function Mutations." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.1379.

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Abstract Context: Loss-of-function mutations in the maternally imprinted Makorin RING-finger 3 (MKRN3) gene (15q11.2) are the most prevalent cause of familial central precocious puberty (CPP). Objectives: To analyze the phenotypes of a large cohort of children with CPP due to MKRN3 mutations and to compare them with the phenotypes of idiopathic CPP. Setting and Participants: We studied 73 individuals from 37 families with mutations in MKRN3 originating from nine different countries. The phenotypes of these patients at initial diagnosis were compared to a cohort of 124 patients with idiopathic CPP. Additionally, expression of nine different genes implicated with pubertal timing, including MKRN3, was performed in the hypothalamus of female mice in different phases of sexual maturation. Results: Nineteen different heterozygous, paternally inherited mutations in MKRN3 were identified in 73 patients with CPP (48 girls and 25 boys). Six MKRN3 mutations were frameshifts, one introduced a premature stop codon, 11 were missense mutations predicted to be pathogenic, and one was a deletion in the promoter region. A frameshift mutation affecting codon 161 in the amino terminal region of the protein was the most frequent MKRN3 defect (46%), representing a hotspot region. Among the cohort with MKRN3 mutations, first pubertal signs occurred at 6·2 ± 1·2 years in girls and 7·6 ± 1·4 years in boys. Patients harboring severe frameshift/nonsense mutations did not differ significantly in any clinical or hormonal parameters compared to the 20 patients with missense variants. However, when the 48 girls with MKRN3 mutations were compared with 124 idiopathic CPP girls, some parameters could be considered as possible predictors of the genetic cause: a lower age at first medical appointment (7·1 ± 1·1 in the MKRN3 group vs. 8·0 ± 2 years in the idiopathic group; p< 0.001) and a shorter time interval between puberty onset and medical assistance (0·8 ± 0·8 vs 2·2 ± 2·1 years; p< 0.001). Interestingly, the other predictor of MKRN3 mutations was a higher basal FSH level (5·1 ± 2·3 vs 3·9 ± 2·7 IU/L; p = 0.017) at first evaluation, although no cutoff value yielded good accuracy. Patients originating from European/Mediterranean countries were more likely to have missense variants (56% of all mutations) than North American and South American (23%) counterparts (p <0.001). Mouse Mkrn3 mRNA levels in the arcuate nucleus were highest in the prepubertal phase when compared with expression of other genes and Mkrn3 decreased progressively through puberty and adult ages. Conclusions: Different types of loss-of-function MKRN3 mutations were associated with premature sexual development in both sexes. Their phenotypes were relatively uniform, regardless of the mutation type. Clinical features of children with MKRN3 mutations were similar to the idiopathic CPP group.

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