Abstract
Objectives
Makorin ring finger protein 3 (MKRN3) is associated with the initiation of puberty, and loss of function mutation of MKRN3 is the most common genetic cause of central precocious puberty (CPP). A recent study reported that MKRN3 interacts with and suppresses neural pentraxin-1 precursor (NPTX1) activity via polyubiquitination during early puberty in the mouse hypothalamus. This study investigated the correlation between serum NPTX1 and MKRN3 in CPP girls and predicted the potential role of NPTX1 in pubertal progression.
Methods
In this case–control study, we examined 34 girls diagnosed with CPP and 34 healthy prepubertal girls. Anthropometric and hormonal parameters were measured and serum levels of NPTX1 and MKRN3 were evaluated with commercial enzyme-linked immunosorbent assay kits.
Results
Serum MKRN3 level decreased significantly in CPP patients compared to controls (344.48 ± 333.77 and 1295.21 ± 780.80 pg/mL, respectively, p<0.001). Serum MKRN3 tended to decrease as Tanner breast stage increased. However, no significant difference was observed in serum NPTX1 levels between patients and controls (20.14 ± 31.75 ng/mL and 12.93 ± 8.28 ng/mL, respectively, p=0.248). The serum level of NPTX1 did not change significantly with the Tanner breast stage. Serum NPTX1 was correlated with the height standard deviation score (r=0.255; p<0.05), but was not correlated with serum MKRN3 level or the others. Conclusion: Although serum NPTX1 level was independent of serum MKRN3 level, the possibility they might be involved in the progression of puberty or CPP remains. Further research is needed to determine their role in the hypothalamus.
Funding source: Soonchunhyang University Research Fund
Acknowledgments
This work was supported by the Soonchunhyang University Research Fund
Research funding: None declared.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Competing interests: The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Ethical approval: This study protocol was approved by the Institutional Review Board of the Hallym Medical Center (KANGDONG 2016-11-003). Consent was obtained from each patient or subject after a full explanation of the purpose and nature of the procedures.
References
1. Herbison, AE. Genetics of puberty. Horm Res 2007;68:75–9. https://doi.org/10.1159/000110583.Search in Google Scholar PubMed
2. Carel, JC, Léger, J. Precocious puberty. N Engl J Med 2008;358:2366–77. https://doi.org/10.1056/nejmcp0800459.Search in Google Scholar
3. Gray, TA, Hernandez, L, Carey, AH, Schaldach, MA, Smithwick, MJ, Rus, K, et al.. The ancient source of a distinct gene family encoding proteins featuring RING and C(3)H zinc-finger motifs with abundant expression in developing brain and nervous system. Genomics 2000;66:76–86. https://doi.org/10.1006/geno.2000.6199.Search in Google Scholar PubMed
4. Abreu, AP, Dauber, A, Macedo, DB, Noel, SD, Brito, VN, Gill, JC, et al.. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 2013;368:2467–75. https://doi.org/10.1056/nejmoa1302160.Search in Google Scholar PubMed PubMed Central
5. Valadares, LP, Meireles, CG, De Toledo, IP, Santarem de Oliveira, R, Gonçalves de Castro, LC, Abreu, AP, et al.. MKRN3 mutations in central precocious puberty: a systematic review and meta-analysis. J Endocr Soc 2019;3:979–95. https://doi.org/10.1210/js.2019-00041.Search in Google Scholar PubMed PubMed Central
6. Hagen, CP, Sørensen, K, Mieritz, MG, Johannsen, TH, Almstrup, K, Juul, A. Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls. J Clin Endocrinol Metab 2015;100:1920–6. https://doi.org/10.1210/jc.2014-4462.Search in Google Scholar PubMed
7. Busch, AS, Hagen, CP, Almstrup, K, Juul, A. Circulating MKRN3 levels decline during puberty in healthy boys. J Clin Endocrinol Metab 2016;101:2588–93. https://doi.org/10.1210/jc.2016-1488.Search in Google Scholar PubMed
8. Omeis, IA, Hsu, YC, Perin, MS. Mouse and human neuronal pentraxin 1 (NPTX1): conservation, genomic structure, and chromosomal localization. Genomics 1996;36:543–5. https://doi.org/10.1006/geno.1996.0503.Search in Google Scholar PubMed
9. Parent, AS, Matagne, V, Westphal, M, Heger, S, Ojeda, S, Jung, H. Gene expression profiling of hypothalamic hamartomas: a search for genes associated with central precocious puberty. Horm Res 2008;69:114–23. https://doi.org/10.1159/000111815.Search in Google Scholar PubMed
10. Shimogori, T, Lee, DA, Miranda-Angulo, A, Yang, Y, Wang, H, Jiang, L, et al.. A genomic atlas of mouse hypothalamic development. Nat Neurosci 2010;13:767–75. https://doi.org/10.1038/nn.2545.Search in Google Scholar PubMed PubMed Central
11. Liu, H, Kong, X, Chen, F. Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. Oncotarget 2017;8:85102–9. https://doi.org/10.18632/oncotarget.19347.Search in Google Scholar PubMed PubMed Central
12. Greulich, WW, Pyle, SI. Radiographic atlas of skeletal development of the hand and wrist. Am J Med Sci 1959;238:393. https://doi.org/10.1097/00000441-195909000-00030.Search in Google Scholar
13. Moon, JS, Lee, SY, Nam, CM, Choi, JM, Choe, BK, Seo, JW, et al.. Korean National Growth Charts: review of developmental process and an outlook. Korean J Pediatr 2008;51:1–25.10.3345/kjp.2008.51.1.1Search in Google Scholar
14. Abreu, AP, Macedo, DB, Brito, VN, Kaiser, UB, Latronico, AC. A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 2015;54:R131–9. https://doi.org/10.1530/jme-14-0315.Search in Google Scholar
15. Macedo, DB, Abreu, AP, Reis, AC, Montenegro, LR, Dauber, A, Beneduzzi, D, et al.. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 2014;99:E1097–103. https://doi.org/10.1210/jc.2013-3126.Search in Google Scholar PubMed PubMed Central
16. Böhne, A, Darras, A, D’Cotta, H, Baroiller, JF, Galiana-Arnoux, D, Volff, JN. The vertebrate makorin ubiquitin ligase gene family has been shaped by large-scale duplication and retroposition from an ancestral gonad-specific, maternal-effect gene. BMC Genom 2010;11:721. https://doi.org/10.1186/1471-2164-11-721.Search in Google Scholar PubMed PubMed Central
17. Jong, MT, Gray, TA, Ji, Y, Glenn, CC, Saitoh, S, Driscoll, DJ, et al.. A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum Mol Genet 1999;8:783–93. https://doi.org/10.1093/hmg/8.5.783.Search in Google Scholar PubMed
18. Jeong, HR, Lee, HJ, Shim, YS, Kang, MJ, Yang, S, Hwang, IT. Serum Makorin ring finger protein 3 values for predicting Central precocious puberty in girls. Gynecol Endocrinol 2019;35:732–6. https://doi.org/10.1080/09513590.2019.1576615.Search in Google Scholar PubMed
19. Schlimgen, AK, Helms, JA, Vogel, H, Perin, MS. Neuronal pentraxin, a secreted protein with homology to acute phase proteins of the immune system. Neuron 1995;14:519–26. https://doi.org/10.1016/0896-6273(95)90308-9.Search in Google Scholar PubMed
20. Kirkpatrick, LL, Matzuk, MM, Dodds, DC, Perin, MS. Biochemical interactions of the neuronal pentraxins. Neuronal pentraxin (NP) receptor binds to taipoxin and taipoxin-associated calcium-binding protein 49 via NP1 and NP2. J Biol Chem 2000;275:17786–92. https://doi.org/10.1074/jbc.m002254200.Search in Google Scholar
21. Sia, GM, Béïque, JC, Rumbaugh, G, Cho, R, Worley, PF, Huganir, RL. Interaction of the N-terminal domain of the AMPA receptor GluR4 subunit with the neuronal pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 2007;55:87–102. https://doi.org/10.1016/j.neuron.2007.06.020.Search in Google Scholar PubMed
22. Xu, D, Hopf, C, Reddy, R, Cho, RW, Guo, L, Lanahan, A, et al.. Narp and NP1 form heterocomplexes that function in developmental and activity-dependent synaptic plasticity. Neuron 2003;39:513–28. https://doi.org/10.1016/s0896-6273(03)00463-x.Search in Google Scholar PubMed
23. Pribiag, H, Stellwagen, D. Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 2014;78:13–22. https://doi.org/10.1016/j.neuropharm.2013.06.008.Search in Google Scholar PubMed
24. Boles, NC, Hirsch, SE, Le, S, Corneo, B, Najm, F, Minotti, AP, et al.. NPTX1 regulates neural lineage specification from human pluripotent stem cells. Cell Rep 2014;6:724–36. https://doi.org/10.1016/j.celrep.2014.01.026.Search in Google Scholar PubMed
25. Cummings, DM, Benway, TA, Ho, H, Tedoldi, A, Fernandes Freitas, MM, Shahab, L, et al.. Neuronal and peripheral pentraxins modify glutamate release and may interact in blood-brain barrier failure. Cerebr Cortex 2017;27:3437–48. https://doi.org/10.1093/cercor/bhx046.Search in Google Scholar PubMed
26. Smyth, C, Wilkinson, M. A critical period for glutamate receptor-mediated induction of precocious puberty in female rats. J Neuroendocrinol 1994;6:275–84. https://doi.org/10.1111/j.1365-2826.1994.tb00583.x.Search in Google Scholar PubMed
27. Bourguignon, JP, Gérard, A, Franchimont, P. Direct activation of gonadotropin-releasing hormone secretion through different receptors to neuroexcitatory amino acids. Neuroendocrinology 1989;49:402–8. https://doi.org/10.1159/000125145.Search in Google Scholar PubMed
28. Medhamurthy, R, Dichek, HL, Plant, TM, Bernardini, I, Cutler, GBJr. Stimulation of gonadotropin secretion in prepubertal monkeys after hypothalamic excitation with aspartate and glutamate. J Clin Endocrinol Metab 1990;71:1390–2. https://doi.org/10.1210/jcem-71-5-1390.Search in Google Scholar PubMed
29. Bettendorf, M, de Zegher, F, Albers, N, Hart, CS, Kaplan, SL, Grumbach, MM. Acute N-methyl-D,L-aspartate administration stimulates the luteinizing hormone releasing hormone pulse generator in the ovine fetus. Horm Res 1999;51:25–30. https://doi.org/10.1159/000023309.Search in Google Scholar PubMed
© 2020 Walter de Gruyter GmbH, Berlin/Boston
