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MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study

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Abstract

Purpose

Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty.

Methods

We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2–8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2–8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9–14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients.

Results

No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:−0.35; p:0.02), Luteinizing Hormone (r:−0.35; p:0.03), FSH (r:−0.37; p:0.02), and (17)estradiol (r: −0.36; p:0.02).

Conclusions

We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small.

In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

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References

  1. E. Terasawa, D.L. Fernandez, Neurobiological mechanisms of the onset of puberty in primates. Endocr. Rev. 22, 111–151 (2001)

    CAS  PubMed  Google Scholar 

  2. L. de Vries, A. Kauschansky, M. Shohat, M. Phillip, Familial central precocious puberty suggests autosomal dominant inheritance. J. Clin. Endocrinol. Metab. 89, 1794–1800 (2004)

    Article  PubMed  Google Scholar 

  3. Z.K. Gajdos, J.N. Hirschhorn, M.R. Palmert, What controls the timing of puberty? An update on progress from genetic investigation. Curr. Opin. Endocrinol. Diabetes. Obes. 16, 16–24 (2009)

    Article  PubMed  Google Scholar 

  4. M.G. Teles, S.D. Bianco, V.N. Brito, E.B. Trarbach, W. Kuohung, S. Xu, S.B. Seminara, B.B. Mendonca, U.B. Kaiser, A.C. Latronico, A GPR54-activating mutation in a patient with central precocious puberty. N. Engl. J. Med. 358, 709–715 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. L.G. Silveira, S.D. Noel, A.P. Silveira-Neto, A.P. Abreu, V.N. Brito, M.G. Santos, S.D. Bianco, W. Kuohung, S. Xu, M. Gryngarten, M.E. Escobar, I.J. Arnhold, B.B. Mendonca, U.B. Kaiser, A.C. Latronico, Mutations of the KISS1 gene in disorders of puberty. J. Clin. Endocrinol. Metab. 95, 2276–2280 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. A.P. Abreu, A. Dauber, D.B. Macedo, S.D. Noel, V.N. Brito, J.C. Gill, P. Cukier, I.R. Thompson, V.M. Navarro, P.C. Gagliardi, T. Rodrigues, C. Kochi, C.A. Longui, D. Beckers, F. de Zegher, L.R. Montenegro, B.B. Mendonca, R.S. Carroll, J.N. Hirschhorn, A.C. Latronico, U.B. Kaiser, Central precocious puberty caused by mutations in the imprinted gene MKRN3. N. Engl. J. Med. 368, 2467–2475 (2013)

    Article  CAS  PubMed  Google Scholar 

  7. D.S. Bessa, D.B. Macedo, V.N. Brito, M.M. França, L.R. Montenegro, M.C. Silva, L.G. Silveira, T. Hummel, I. Bergadá, D. Braslavsky, A.P. Abreu, A. Dauber, B.B. Mendonca, U.B. Kaiser, A.C. Latronico High frequency of MKRN3 mutations in male central precocious puberty previously classified as Idiopathic. Neuroendocrinology (2016). doi:10.1159/00044693

  8. A. Grandone, G. Cantelmi, G. Cirillo, P. Marzuillo, C. Luongo, E. Miraglia del Giudice, L. Perrone, A case of familial central precocious puberty caused by a novel mutation in the makorin RING finger protein 3 gene. BMC. Endocr. Disord. 15, 60 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  9. D. Simon, I. Ba, N. Mekhail, E. Ecosse, A. Paulsen, D. Zenaty, M. Houang, M. Jesuran Perelroizen, G.P. de Filippo, M. Salerno, G. Simonin, R. Reynaud, J.C. Carel, J. Léger, N. de Roux, Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. Eur. J. Endocrinol. 174, 1–8 (2016)

    CAS  PubMed  Google Scholar 

  10. J. Känsäkoski, T. Raivio, A. Juul, J. Tommiska, A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty. Pediatr. Res. 78, 709–711 (2015)

    Article  PubMed  Google Scholar 

  11. V. Neocleous, C. Shammas, M.M. Phelan, S. Nicolaou, L.A. Phylactou, N. Skordis, In silico analysis of a novel MKRN3 missense mutation in familial central precocious puberty. Clin. Endocrinol. 84, 80–84 (2016)

    Article  CAS  Google Scholar 

  12. H.S. Lee, H.S. Jin, Y.S. Shim, H.R. Jeong, E. Kwon, V. Choi, M.C. Kim, I.S. Chung, S.Y. Jeong, J.S. Hwang, Low frequency of MKRN3 mutations in central precocious puberty among Korean girls. Horm. Metab. Res. 48, 118–122 (2016)

    CAS  PubMed  Google Scholar 

  13. L. de Vries, G. Gat-Yablonski, N. Dror, A. Singer, M. Phillip, A novel MKRN3 missense mutation causing familial precocious puberty. Hum. Reprod. 29, 2838–2843 (2014)

    Article  PubMed  Google Scholar 

  14. D.B. Macedo, A.P. Abreu, A.C. Reis, L.R. Montenegro, A. Dauber, D. Beneduzzi, P. Cukier, L.F. Silveira, M.G. Teles, R.S. Carroll, G.G. Junior, G.G. Filho, Z. Gucev, I.J. Arnhold, M. de Castro, A.C. Moreira, C.E. Martinelli Jr., J.N. Hirschhorn, B.B. Mendonca, V.N. Brito, S.R. Antonini, U.B. Kaiser, A.C. Latronico, 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. 99, 1097–1103 (2014)

    Article  Google Scholar 

  15. N. Settas, C. Dacou-Voutetakis, M. Karantza, C. Kanaka-Gantenbein, G.P. Chrousos, A. Voutetakis, Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene. J. Clin. Endocrinol. Metab. 99, 647–651 (2014)

    Article  Google Scholar 

  16. M.T. Jong, T.A. Gray, Y. Ji, C.C. Glenn, S. Saitoh, D.J. Driscoll, R.D. Nicholls, A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum. Mol. Genet. 8, 783–793 (1999)

    Article  CAS  PubMed  Google Scholar 

  17. C.P. Hagen, K. Sørensen, M.G. Mieritz, T.H. Johannsen, K. Almstrup, A. Juul, Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls. J. Clin. Endocrinol. Metab. 100, 1920–1926 (2015)

    Article  CAS  PubMed  Google Scholar 

  18. A.S. Busch, C.P. Hagen, K. Almstrup, A. Juul, Circulating MKRN3 levels decline during puberty in healthy boys. J. Clin. Endocrinol. Metab. 101, 2588–2593 (2016)

    Article  CAS  PubMed  Google Scholar 

  19. T. Varimo, L. Dunkel, K. Vaaralahti, P.J. Miettinen, M. Hero, T. Raivio, Circulating makorin ring finger protein 3 levels decline in boys before the clinical onset of puberty. Eur. J. Endocrinol. 174, 785–790 (2016)

    Article  CAS  PubMed  Google Scholar 

  20. C.P. Hagen, L. Aksglaede, K. Sørensen, A. Mouritsen, A.M. Andersson, J.H. Petersen, K.M. Main, A. Juul, Individual serum levels of anti-Müllerian hormone in healthy girls persist through childhood and adolescence: a longitudinal cohort study. Hum. Reprod. 27, 861–866 (2012)

    Article  CAS  PubMed  Google Scholar 

  21. H. Lashen, D.B. Dunger, A. Ness, K.K. Ong, Peripubertal changes in circulating antimüllerian hormone levels in girls. Fertil. Steril. 99, 2071–2075 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. T.J. Cole, The LMS method for constructing normalized growth standards. Eur. J. Clin. Nutr. 44, 45–60 (1990)

    CAS  PubMed  Google Scholar 

  23. J.M. Tanner, R.H. Whitehouse, Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch. Dis. Child. 51, 170–179 (1976)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. E.A. Resende, B.H. Lara, J.D. Reis, B.P. Ferreira, G.A. Pereira, M.F. Borges, Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children. J. Clin. Endocrinol. Metab. 92, 1424–1429 (2007)

    Article  CAS  PubMed  Google Scholar 

  25. M. Tena-Sempere, Keeping puberty on time: novel signals and mechanisms involved. Curr. Top. Dev. Biol. 105, 299–329 (2013)

    Article  CAS  PubMed  Google Scholar 

  26. C.P. Hagen, K. Sørensen, R.A. Anderson, A. Juul, Serum levels of antimüllerian hormone in early maturing girls before, during, and after suppression with GnRH agonist. Fertil. Steril. 98, 1326–1330 (2012)

    Article  CAS  PubMed  Google Scholar 

  27. A. German, M. Shmoish, Z. Hochberg, Predicting pubertal development by infantile and childhood height, BMI, and adiposity rebound. Pediatr. Res. 78, 445–450 (2015)

    Article  PubMed  Google Scholar 

  28. H.S. Lee, J.S. Yoon, J.K. Roh, J.S. Hwang, Changes in body mass index during gonadotropin-releasing hormone agonist treatment for central precocious puberty and early puberty. Endocrine 54, 497–503 (2016)

    Article  CAS  PubMed  Google Scholar 

  29. A. Christoforidis, N. Skordis, P. Fanis, M. Dimitriadou, M. Sevastidou, M.M. Phelan, V. Neocleous, L A. Phylactou A novel MKRN3 nonsense mutation causing familial central precocious puberty. Endocrine (2017). doi:10.1007/s12020-017-1232-6

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Authors and Affiliations

  1. Department of Woman, Child, General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy

    Anna Grandone, Grazia Cirillo, Marcella Sasso, Carlo Capristo, Pierluigi Marzuillo, Caterina Luongo, Giuseppina Rosaria Umano, Adalgisa Festa, Ruggero Coppola, Emanuele Miraglia del Giudice & Laura Perrone

  2. Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy

    Gianluca Tornese

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  1. Anna Grandone
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  2. Grazia Cirillo
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Correspondence to Pierluigi Marzuillo.

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The authors declare that they have no competing interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Grandone, A., Cirillo, G., Sasso, M. et al. MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study. Endocrine 59, 203–208 (2018). https://doi.org/10.1007/s12020-017-1281-x

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  • DOI: https://doi.org/10.1007/s12020-017-1281-x

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