# Deciphering the functional role of MKRN3 in puberty and reproduction

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $606,425

## Abstract

The hypothalamic-pituitary-gonadal (HPG) axis regulates puberty initiation and reproductive function. The timing
of puberty initiation is associated with risks for development of a wide range of diseases in adulthood, including
obesity, diabetes, cardiovascular/cardiometabolic disorders, and cancer. Pubertal development is a complex
process that is regulated by the activity of the HPG axis and is influenced by genetic, nutritional and
environmental factors. The HPG axis is active in the embryonic and neonatal stages of life; it is then suppressed
during childhood until reactivation at the time of puberty. Premature re-activation of the HPG axis results in
central precocious puberty (CPP). The precise mechanisms that regulate GnRH secretion to constrain the HPG
axis during infancy and childhood and subsequently trigger puberty initiation remain elusive. Genetic studies of
patients with reproductive disorders have led to identification of genes that regulate GnRH secretion and have
increased our understanding of the neuroendocrine regulation of reproductive function. We used an unbiased
approach to identify loss-of-function mutations in MKRN3 in patients with CPP, linking this imprinted gene with
the reproductive axis for the first time. Mutations in MKRN3 are now recognized to be the most common genetic
cause of CPP. The long-term goal of this project is to elucidate the molecular, cellular, and physiologic
mechanisms by which MKRN3 controls the timing of puberty onset. We hypothesize that MKRN3 acts in the
hypothalamus to inhibit the reproductive axis. In the first aim of this proposal, we will study the roles and
mechanisms of action of MKRN3 in male and female neural development and synaptic plasticity during puberty.
In the second aim, we will examine candidate targets of MKRN3, including KISS1, NKB, IGF2BP1 and LIN28B,
as well as mRNA targets, in the regulation of the reproductive axis. In the third aim, we will identify new MKRN3
targets and leverage mutations in key protein domains identified in patients with CPP to investigate the roles of
different MKRN3 domains in protein function. The successful completion of these aims will help us to understand
the actions of MKRN3, a novel regulator of GnRH re-activation, in the neuroendocrine control of pubertal timing.
A better understanding of the role of MRKN3 may also identify novel factors involved in the neuroendocrine
control of reproduction and lead to the development of new tools for the management of pubertal and
reproductive disorders.

## Key facts

- **NIH application ID:** 10873798
- **Project number:** 5R01HD082314-08
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Ursula B. Kaiser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,425
- **Award type:** 5
- **Project period:** 2015-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873798

## Citation

> US National Institutes of Health, RePORTER application 10873798, Deciphering the functional role of MKRN3 in puberty and reproduction (5R01HD082314-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873798. Licensed CC0.

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