A new pathway in the control of the initiation of puberty: the MKRN3 gene

Abstract

Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The role of MKRN3, 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 deleterious MKRN3 mutations in five families with central precocious puberty (CPP) using whole-exome sequencing analysis. Since then, additional loss-of-function mutations of MKRN3 have 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 of MKRN3 (a maternally imprinted gene). Interestingly, the hypothalamic Mkrn3 mRNA 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 that MKRN3 plays an inhibitory role in the reproductive axis to represent a new pathway in pubertal regulation.

Keywords: gonadotropins; hypothalamus and neuroendocrinology; mutations; secretion.

Figure 1. MKRN3 protein structure and mutations identified in patients with central precocious puberty

(Zn) zinc; (H) histidine; (C) cysteine. The three C3H zinc finger motifs are shown in red, the C3HC4 RING finger motif is in blue, and the MKRN-specific Cys–His domain is shown in green. The numbers correspond to the amino acid positions in the protein. Blue mutation labels and arrows indicate the location of frameshift mutations; pink mutation labels and arrows indicate the location of the missense mutations.

Figure 2. MKRN1 and MKRN3 protein sequence alignment

The two protein sequences share high homology and similarity, especially in the RING finger domains. Bold letters represent conserved amino acids, and squares similar amino acids. Sections highlighted in red represent the three zinc fingers C3H motifs, in yellow the MKRN-specific Cys-His motif, and in green the RING finger domain. MKRN1 NCBI Reference Sequence NP_038474, UniProtKB/Swiss-Prot: Q9UHC7.3. MKRN3 NP_005655.1 and UniProtKB/Swiss-Prot Q13064.1.

Figure 3. Schematic representation of MKRN3 mechanism of action

Human and mouse studies suggest that MKRN3 acts as an inhibitor of GnRH secretion during childhood (diagram on A), and that a decrease in MKRN3 expression is associated with an increase in GnRH stimulatory factors and/or GnRH resulting in puberty initiation (diagram on B). NKB, neurokinin B; − inhibition, + stimulation. ↑ increase ↓ decrease.