Ann Pediatr Endocrinol Metab.  2016 Jun;21(2):66-69. 10.6065/apem.2016.21.2.66.

An update on the genetic causes of central precocious puberty

Affiliations
  • 1Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea. ylshin@schmc.ac.kr

Abstract

Central precocious puberty (CPP) is caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, nutritional, and environmental factors play a crucial role in determining pubertal timing. Recently mutations in kisspeptin (KISS1), kisspeptin receptor (KISS1R), and makorin RING finger protein 3 (MKRN3) genes have been identified as genetic causes of CPP. In particular, the MKRN3 gene is known to affect pubertal initiation. The MKRN3 gene is located on chromosome 15q11-q13 in the Prader-Willi syndrome (PWS) critical region. MKRN3 deficiency, due to a loss of function mutation, leads to the withdrawal of hypothalamic inhibition and prompts pulsatile gonadotropin-releasing hormone secretion, resulting in precocious puberty. The exact functions of these genes associated with CPP are still not well understood. Larger studies are required to discover the mechanisms involved in pubertal development.

Keyword

Central precocious puberty; Kisspeptins; MKRN3 gene; Mutation

MeSH Terms

Fingers
Gonadotropin-Releasing Hormone
Kisspeptins
Prader-Willi Syndrome
Puberty, Precocious*
Gonadotropin-Releasing Hormone
Kisspeptins

Figure

  • Fig. 1 MKRN3 domains (3 C3H zinc finger motifs, 1 C3HC4 RING zinc finger motif, and 1 MKRN specific Cys-His domain) and MKRN3 mutations identified in patients with central precocious puberty. The numbers correspond to the amino acid positions in the protein. 8 frameshift mutations (blue), 10 missense mutations (red) and 3 nonsense mutations (green) are shown.


Cited by  1 articles

Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders
Maki Fukami, Mami Miyado
Ann Pediatr Endocrinol Metab. 2017;22(2):90-94.    doi: 10.6065/apem.2017.22.2.90.


Reference

1. Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev. 2001; 22:111–151. PMID: 11159818.
Article
2. Partsch CJ, Heger S, Sippell WG. Management and outcome of central precocious puberty. Clin Endocrinol (Oxf). 2002; 56:129–148. PMID: 11874402.
Article
3. Carel JC, Leger J. Clinical practice: precocious puberty. N Engl J Med. 2008; 358:2366–2377. PMID: 18509122.
4. Gajdos ZK, Hirschhorn JN, Palmert MR. What controls the timing of puberty? An update on progress from genetic investigation. Curr Opin Endocrinol Diabetes Obes. 2009; 16:16–24. PMID: 19104234.
Article
5. Palmert MR, Boepple PA. Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab. 2001; 86:2364–2368. PMID: 11397824.
Article
6. de Vries L, Kauschansky A, Shohat M, Phillip M. Familial central precocious puberty suggests autosomal dominant inheritance. J Clin Endocrinol Metab. 2004; 89:1794–1800. PMID: 15070947.
Article
7. Brito VN, Mendonca BB, Guilhoto LM, Freitas KC, Arnhold IJ, Latronico AC. Allelic variants of the gamma-aminobutyric acid-A receptor alpha1-subunit gene (GABRA1) are not associated with idiopathic gonadotropin-dependent precocious puberty in girls with and without electroencephalographic abnormalities. J Clin Endocrinol Metab. 2006; 91:2432–2436. PMID: 16569738.
Article
8. Freitas KC, Ryan G, Brito VN, Tao YX, Costa EM, Mendonca BB, et al. Molecular analysis of the neuropeptide Y1 receptor gene in human idiopathic gonadotropin-dependent precocious puberty and isolated hypogonadotropic hypogonadism. Fertil Steril. 2007; 87:627–634. PMID: 17140570.
Article
9. Silveira-Neto AP, Leal LF, Emerman AB, Henderson KD, Piskounova E, Henderson BE, et al. Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty. Horm Res Paediatr. 2012; 78:144–150. PMID: 22964795.
Article
10. Tusset C, Noel SD, Trarbach EB, Silveira LF, Jorge AA, Brito VN, et al. Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders. Arq Bras Endocrinol Metabol. 2012; 56:646–652. PMID: 23329188.
Article
11. Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008; 358:709–715. PMID: 18272894.
Article
12. Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010; 95:2276–2280. PMID: 20237166.
Article
13. 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; 368:2467–2475. PMID: 23738509.
Article
14. Navarro VM, Castellano JM, Garcia-Galiano D, Tena-Sempere M. Neuroendocrine factors in the initiation of puberty: the emergent role of kisspeptin. Rev Endocr Metab Disord. 2007; 8:11–20. PMID: 17340172.
Article
15. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003; 349:1614–1627. PMID: 14573733.
Article
16. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003; 100:10972–10976. PMID: 12944565.
Article
17. Bianco SD, Vandepas L, Correa-Medina M, Gereben B, Mukherjee A, Kuohung W, et al. KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology. 2011; 152:1616–1626. PMID: 21285314.
Article
18. Leka-Emiri S, Louizou E, Kambouris M, Chrousos G, De Roux N, Kanaka-Gantenbein C. Absence of GPR54 and TACR3 mutations in sporadic cases of idiopathic central precocious puberty. Horm Res Paediatr. 2014; 81:177–181. PMID: 24434351.
Article
19. 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; 8:783–793. PMID: 10196367.
Article
20. Crino A, Di Giorgio G, Schiaffini R, Fierabracci A, Spera S, Maggioni A, et al. Central precocious puberty and growth hormone deficiency in a boy with Prader-Willi syndrome. Eur J Pediatr. 2008; 167:1455–1458. PMID: 18301920.
Article
21. Lee HS, Hwang JS. Central precocious puberty in a girl with Prader-Willi syndrome. J Pediatr Endocrinol Metab. 2013; 26:1201–1204. PMID: 23740678.
Article
22. Settas N, Dacou-Voutetakis C, Karantza M, Kanaka-Gantenbein C, Chrousos GP, Voutetakis A. 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. 2014; 99:E647–E651. PMID: 24438377.
Article
23. 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–E1103. PMID: 24628548.
Article
24. de Vries L, Gat-Yablonski G, Dror N, Singer A, Phillip M. A novel MKRN3 missense mutation causing familial precocious puberty. Hum Reprod. 2014; 29:2838–2843. PMID: 25316453.
Article
25. Schreiner F, Gohlke B, Hamm M, Korsch E, Woelfle J. MKRN3 mutations in familial central precocious puberty. Horm Res Paediatr. 2014; 82:122–126. PMID: 25011910.
Article
26. Grandone A, Cantelmi G, Cirillo G, Marzuillo P, Luongo C, Miraglia del Giudice E, et al. A case of familial central precocious puberty caused by a novel mutation in the makorin RING finger protein 3 gene. BMC Endocr Disord. 2015; 15:60. PMID: 26499472.
Article
27. Simon D, Ba I, Mekhail N, Ecosse E, Paulsen A, Zenaty D, et al. Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. Eur J Endocrinol. 2016; 174:1–8. PMID: 26431553.
Article
28. Lee HS, Jin HS, Shim YS, Jeong HR, Kwon E, Choi V, et al. Low frequency of MKRN3 mutations in central precocious puberty among Korean girls. Horm Metab Res. 2016; 48:118–122. PMID: 25938887.
Article
29. Neocleous V, Shammas C, Phelan MM, Nicolaou S, Phylactou LA, Skordis N. In silico analysis of a novel MKRN3 missense mutation in familial central precocious puberty. Clin Endocrinol (Oxf). 2016; 84:80–84. PMID: 26173472.
Article
30. Ojeda SR, Lomniczi A. Puberty in 2013: unravelling the mystery of puberty. Nat Rev Endocrinol. 2014; 10:67–69. PMID: 24275741.
31. 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; 100:1920–1926. PMID: 25695892.
Article
Full Text Links
  • APEM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr