# Characterization of the role of maternal effect gene Nlrp2 in reproduction

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $405,360

## Abstract

PROJECT SUMMARY
Maternal mutations in human NLRP7 cause pregnancies recurrent hydatidiform molar pregnancies with
imprinting defects. Maternal mutations in its highly homologous neighboring gene NLRP2, cause a multi-locus
imprinting disorder (MLID) that manifests as Beckwith-Wiedemann syndrome in offspring. Both are associated
with abnormal DNA methylation of maternally imprinted genes. Rodents have the Nlrp2 gene, but no Nlrp7. We
hypothesized that Nlrp2 may combine functions of both human homologs and generated a Nlrp2-mutant mouse
model to study the mechanisms by which its maternal inactivation causes the observed offspring and placental
abnormalities. We found that NLRP2 protein is a new member of the subcortical maternal complex (SCMC), a
cytoplasmic complex in oocytes that persists in preimplantation embryos with a presumed role in maternal-to-
zygote transition and zygotic genome activation, which are the processes by which embryos switch from reliance
on maternally contributed transcripts and proteins to their own transcription and translation. We found that a
maternal-effect mutation in Nlrp2 disrupts the SCMC, causing Nlrp2-null females to produce fewer and smaller
litters with offspring that have birth defects, growth abnormalities, and imprinting defects. In vitro cultured
embryos of these Nlrp2-null females have a more severe phenotype with early cleavage-stage arrest. These
data for the first time link the SCMC to imprinting reprogramming and indicate that Nlrp2-null mice are an
excellent model to study the mechanisms of this interaction. They support the overarching goal of this project, to
characterize how maternal loss of NLRP2, a new SCMC protein, alters imprinting in offspring, and how this leads
to a range of reproductive phenotypes. Towards this goal, for specific aim 1, we will characterize the cellular and
developmental events in the zygote and preimplantation embryo that are at the origin of the reproductive and
imprinting phenotypes. For specific aim 2, we will investigate the molecular mechanisms that underlie the
reproductive phenotypes of maternal inactivation of Nlrp2 by following up on other interesting early observations,
which include that NLRP2 and DNA-methyltransferase 1 (DNMT1) co-localize in preimplantation embryos, and
that Nlrp2-deficient oocytes have altered gene expression profiles. For specific aim 3 we will characterize in vivo
the variable later developmental abnormalities of embryos and placentas resulting from maternal loss of Nlrp2.
This will increase knowledge on the reproductive disorders caused by maternal effect mutations. All phenotyping
will be complemented by transcriptomics, methylomics and profiling of DNMT1 binding to fully integrate
molecular and phenotypic data. We predict that this work will uncover important new principles of genome
reprogramming during gametogenesis and after fertilization and will clarify how the SCMC affects this process.
The long-term benefit for human health will in...

## Key facts

- **NIH application ID:** 9951085
- **Project number:** 5R01HD092746-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** IGNATIA B VAN DEN VEYVER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,360
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951085

## Citation

> US National Institutes of Health, RePORTER application 9951085, Characterization of the role of maternal effect gene Nlrp2 in reproduction (5R01HD092746-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9951085. Licensed CC0.

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