# Integrative Approaches to Decipher Genetic Determinants of Disease Penetrance in Prokineticin 2 Pathway Related Human Reproductive Disorders

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $339,851

## Abstract

A major challenge in accomplishing genomic precision medicine is the observation that genotype does not
always predict phenotype. Incomplete penetrance and variable expressivity represent two examples of this
phenotypic variability. This complexity is well-illustrated by human mutations in PROK2 (encoding prokineticin
2) and PROKR2 (prokineticin receptor 2), that cause human Isolated GnRH (gonadotropin-releasing hormone)
Deficiency (IGD). Prokineticin 2 signaling is a master regulator of mammalian reproduction and is associated
with neurodevelopmental and neuroendocrine forms of IGD in humans (Kallmann syndrome, and normosmic
IGD, respectively). In addition to this physiologic complexity, PROK2/R2 mutations are predominantly missense
mutations that exhibit either reduced penetrance and/or variable expressivity. The genetic basis of this variability
is not fully understood but allelic heterogeneity and modifier genes have been postulated to account for this
variability. In Specific Aim 1, allelic heterogeneity of human PROKR2 mutations will be examined in vitro, using
PROK2 signaling assays and allele specific expression studies. Whole exome sequencing and SNP genotyping
will identify modifier genes that contribute to disease penetrance and expressivity. PROK2 is also implicated in
diverse physiologic processes such as glucose metabolism, energy balance, food intake, circadian rhythms, pain
modulation, neutrophil chemotaxis and angiogenesis. The human relevance of these pleotropic functions of
PROK2 is yet to be established. In Specific Aim 2, phenomic dissection of humans with PROK2/R2 mutations
will be undertaken to define the pleotropic phenotypes relating to PROK2/R2 mutations in humans. IGD patients
as well as control individuals in a tertiary hospital biobank population will be studied. Reproductive phenotypes
and non-reproductive phenotypes will be charted. Targeted phenotyping will include assessment of glucose
homeostasis and pain modulation in both groups. A phenome-wide association study will be conducted in the
biobank subjects harboring PROK2/R2 mutations. In Specific Aim 3, using a novel PROKR2-cre mouse model,
transcriptomic studies of PROKR2 and GnRH neurons will be done at various developmental timepoints using
temporal inhibition of PROKR2 using chemogenetics. Sexual maturation and fertility of these mice after temporal
PROKR2 inhibition will also be examined. The top genes that are differentially expressed in the murine
transcriptomic experiments will be translationally validated by assessing whether these genes emerge as
modifier genes in the human whole exome sequencing studies. The studies in this proposal have the potential
to unravel novel genetic mechanisms of disease penetrance relating to the PROK2 pathway mutations, uncover
potential pleotropic human phenotypes associated with mutations in this pathway and help deliver personalized
medicine to humans with reproductive disorders and infertility.

## Key facts

- **NIH application ID:** 9936220
- **Project number:** 5R01HD096324-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ravikumar Balasubramanian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,851
- **Award type:** 5
- **Project period:** 2018-09-13 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936220

## Citation

> US National Institutes of Health, RePORTER application 9936220, Integrative Approaches to Decipher Genetic Determinants of Disease Penetrance in Prokineticin 2 Pathway Related Human Reproductive Disorders (5R01HD096324-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936220. Licensed CC0.

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