ESPE Yearbook of Paediatric Endocrinology

J Clin Invest. 2020 Aug 3;130(8):4486–4500. 10.1172/JCI136564. PMID: 32407292 https://www.jci.org/articles/view/136564

In brief: This study in rats and non-human primate models investigated the mechanisms by which MKRN3 regulates pubertal onset in rats and non-human primates.

Comment: Pubertal timing is influenced by genetic, nutritional, environmental and socioeconomic factors. The importance of genetic determinants is clearly illustrated by MKRN3 mutations leading to central precocious puberty (CPP) (1). MKRN3 appears to act as a brake on GnRH secretion during childhood, as loss of function mutations lead to CPP (1) and MKRN3 expression markedly decreases in mouse medial basal hypothalamus before puberty (2). However, the mechanism by which MKRN3 deficiency induces early activation of GnRH secretion remains unknown.

Using rats and non-human primate models, this study characterizes MKRN3 expression and action. The authors confirmed the decrease in MKRN3 expression in the hypothalamus of prepubertal rats and nonhuman primates, as previously reported in mice. This decrease occurs independently of gonadal activation and suggests a primary role for MKRN3 early in life. Although not explored here, such developmental decrease in expression could involve miR30, recently identified as a repressor of MKRN3 (3). The authors found MKRN3 expression in KISS1 neurons and showed its ability to inhibit KISS1 and TAC3 promoter activity. This action requires MKRN3 ubiquitinase activity, as mutations in the RING finger domain prevented MKRN3 inhibitory action on KISS1 and TAC3 promoter activity. This finding is clinically relevant as most of the MKRN3 missense mutations associated with CPP are located in the RING finger domain (1). In summary, this study supports a role for MKRN3 in the central control of GnRH release through the inhibition of KISS1 and TAC3 transcription in Kiss1 neurons.

Reference: 1. Valadares LP, Meireles CG, De Toledo IP, Santarem de Oliveira R, Gonçalves de Castro LC, Abreu AP, Carroll RS, Latronico AC, Kaiser UB, Guerra ENS, Lofrano-Porto A. (2019) MKRN3 Mutations in central precocious puberty: a systematic review and meta-analysis. J Endocr Soc. 3(5):979–995.2. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, Kaiser UB (2013) Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 368(26):2467–2475.4. Heras V, Sangiao-Alvarellos S, Manfredi-Lozano M, Sanchez-Tapia MJ, Ruiz-Pino F, Roa J, Lara-Chica M, Morrugares-Carmona R, Jouy N, Abreu AP, Prevot V, Belsham D, Vazquez MJ, Calzado MA, Pinilla L, Gaytan F, Latronico AC, Kaiser UB, Castellano JM, Tena-Sempere M (2019) Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3. PLoS Biol. 17(11):e3000532.