# The effects of Mkrn3 on delayed puberty

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2024 · $167,940

## Abstract

PROJECT SUMMARY
Puberty is a remarkable time during which the body develops secondary sexual characteristics and becomes
capable of reproduction. Puberty onset is due to a complex interplay of factors, including genetic influences.
Genetic mutations in disorders of puberty, including central precocious puberty (CPP) and delayed puberty,
provide windows into understanding the neuroendocrine mechanisms of puberty and reproduction.
The most common genetic cause of precocious puberty is due to loss-of-function mutations in Makorin Ring
Finger Protein 3 (MKRN3), and accounts for ~40% of familial CPP. The function and regulation of MKRN3 are
not well understood, but its protein structure suggests E3 ubiquitin ligase and RNA binding activities. Expression
of Mkrn3 is high in the mouse hypothalamus and rapidly declines before puberty onset. This supports its role as
the first identified inhibitor of puberty onset, hypothesized to act upstream of GnRH and/or its activators, such as
kisspeptin.
The current proposal aims to explore if alterations in Mkrn3 expression can similarly lead to delayed pubertal
onset using innovative mouse models and human investigation. Preliminary studies demonstrate a delayed
puberty phenotype in wild type female mice injected intracerebroventricularly with a recombinant virus
overexpressing Mkrn3. This current model will be used to explore MKRN3’s mechanism of action, including its
impact on known neuroendocrine players in reproduction. This recombinant virus will be used to assess if Mkrn3
overexpression can also lead to hypogonadotropic hypogonadism postpubertally following bilateral stereotaxic
injection into the arcuate nuclei of the hypothalamus. In a more specific model of overexpression, Mkrn3 will be
selectively overexpressed in kisspeptin neurons using a novel transgenic mouse model to better identify
MKRN3’s targets. Additionally, given the observation in preliminary studies that increases in Mkrn3 expression
can delay puberty onset, a well-characterized cohort of children with delayed puberty will be screened for coding
and non-coding variants in MKRN3 as this has not been previously explored.
Delayed puberty puts children at risk for long-term health risks. Therefore, elucidating the impact and
mechanisms of action of MKRN3 in delaying pubertal onset has important implications for advancing child health,
including improving diagnosis and management of pubertal disorders and can serve as a future therapeutic
target. Using the proposed tools to identify MKRN3’s targets of action is critical to understanding this key player
in the neuroendocrine control of puberty and reproduction.

## Key facts

- **NIH application ID:** 10836005
- **Project number:** 5K08HD100595-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Stephanie Anne Roberts
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $167,940
- **Award type:** 5
- **Project period:** 2021-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836005

## Citation

> US National Institutes of Health, RePORTER application 10836005, The effects of Mkrn3 on delayed puberty (5K08HD100595-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10836005. Licensed CC0.

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