# Neurodevelopmental disorder‐causing GRIN1 Y647S variant alters red blood cell physiology in mice

## TL;DR

A genetic variant linked to a rare brain disorder causes changes in red blood cell function in mice, offering new clues for potential biomarkers.

## Contribution

First genetic evidence that NMDAR gain-of-function alters red blood cell physiology in a mouse model of GRIN Disorder.

## Key findings

- Grin1Y647S/+ mice show increased red blood cell counts and erythropoiesis with normal erythropoietin levels.
- NMDAR-mediated calcium influx is elevated in Grin1Y647S/+ red blood cells, reducing blood viscosity under flow.
- RBC indices in Grin1Y647S/+ mice reflect altered NMDAR function, suggesting potential peripheral biomarkers for GRIN Disorder.

## Abstract

GRIN Disorder is a rare neurodevelopmental disease caused by pathogenic variants in GRIN genes encoding subunits of the N‐methyl‐D‐aspartate receptor (NMDAR). GRIN Disorder presents with a wide spectrum of neurological symptoms and currently lacks effective therapeutics and clinically accessible biomarkers to stratify disease severity or monitor treatment response. While NMDARs are well‐studied in the central nervous system, they are also expressed in peripheral blood cells, including red blood cells (RBCs), where they modulate calcium signaling and cell function. Here we have used well‐established in vivo and ex vivo methods to investigate hematological (primarily RBC‐linked) phenotypes in transgenic mice carrying heterozygous Grin1 Y647S (Grin1Y647S/+) variant. We found that Grin1Y647S/+ mice had slightly increased RBC counts associated with increased erythropoiesis and normal erythropoietin levels. Functional assays revealed increased NMDAR‐mediated calcium influx in Grin1Y647S/+ RBCs, accompanied by reduced blood viscosity under flow conditions. Our findings provide the first genetic evidence that NMDAR gain‐of‐function leads to systemic changes in RBC physiology, which may contribute to core phenotypes of NMDAR‐related disorders. Results point to several RBC indices that reflect altered NMDAR function in Grin1Y647S/+ mice, providing foundational evidence for the development of peripheral blood biomarkers for patients with GRIN Disorder.

Genetically‐modified mice with the Y647S substitution were used to study blood physiology and identify potential biomarkers for GRIN disorder patient stratification. Red blood cells from these mice have increased NMDA receptor mediated calcium influx, indicating a gain‐of‐function phenotype. The physiological impact of NMDAR gain‐of‐function included changes in blood viscosity and RBC number, providing new leads for biomarker discovery.