Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jun;54(3):R131-9.
doi: 10.1530/JME-14-0315.

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

Ana Paula Abreu  1 , Delanie B Macedo  1 , Vinicius N Brito  1 , Ursula B Kaiser  1 , Ana Claudia Latronico  2
Affiliations
Review

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

Ana Paula Abreu et al. J Mol Endocrinol. 2015 Jun.

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.

PubMed Disclaimer

Figures

Figure 1
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
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013;368:2467–2475. - PMC - PubMed
    1. Barabino SM, Hubner W, Jenny A, Minvielle-Sebastia L, Keller W. The 30-kD subunit of mammalian cleavage and polyadenylation specificity factor and its yeast homolog are RNA-binding zinc finger proteins. Genes Dev. 1997;11:1703–1716. - PubMed
    1. Behrends C, Harper JW. Constructing and decoding unconventional ubiquitin chains. Nat Struct Mol Biol. 2011;18:520–528. - PubMed
    1. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009;5:569–576. - PMC - PubMed
    1. Bielinska B, Blaydes SM, Buiting K, Yang T, Krajewska-Walasek M, Horsthemke B, Brannan CI. De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch. Nat Genet. 2000;25:74–78. - PubMed

Publication types