# A molecular pathway that links N-glycosylation to birth defects

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $331,960

## Abstract

Project Summary
A molecular pathway that links N-glycosylation to birth defects
Developmental defects are the leading cause of both fetal loss before birth and infant deaths after birth. The
immense advances in our genetic understanding of mammalian development over the past four decades have
not yet translated into better preventative or therapeutic options for babies with birth defects. Our ability to
address this high unmet need depends critically on the discovery and detailed mechanistic understanding of
molecular and cellular pathways that drive human developmental defects. Working with a multidisciplinary
investigative team that combines expertise in signal transduction, human genetics and bone biology, we have
discovered an novel inter-organelle communication mechanism that links protein N-glycosylation in the
Endoplasmic Reticulum (ER) to the reception of WNT signals at the cell surface. The WNT/β-catenin pathway
is a key cell-cell communication system that regulates tissue patterning during development and regenerative
responses in adults. Human genetic studies from our collaborators show that this ER-based pathway is
disrupted in a severe, deforming subtype of the inherited bone fragility disorder Osteogenesis Imperfecta (OI)
and in subtypes of Congenital Disorders of Glycosylation (CDG), characterized by developmental defects
across tissues. Given that over 25% of proteins encoded in our genomes are N-glycosylated, we propose the
existence of a surveillance mechanism (analogous to the unfolded protein response) that ensures WNT-driven
differentiation is only allowed to proceed if the ER N-glycosylation machinery is intact. The three goals of this
proposal are to delineate the components and transduction mechanisms of this regulated N-glycosylation
pathway, understand its role in osteoblast differentiation and bone matrix production and establish its relevance
to human birth defect syndromes. We use genome-wide CRISPR screens and mass spectrometry to identify
pathway components, gene-editing to disrupt or mutate these components in both cell lines and primary cells
from human OI patients, and mechanistic studies to understand how N-glycosylation in the ER tunes WNT
ligand sensitivity at the cell surface. Successful completion of this project will define a new pathway that
regulates WNT signaling and human development by using N-glycosylation as a regulatory post-translational
modification. More broadly, our work will define a largely unexplored signaling function for N-glycosylation, a
fundamental cell biological process linked to diseases across multiple organ systems.

## Key facts

- **NIH application ID:** 10776891
- **Project number:** 1R01HD113790-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** RAJAT ROHATGI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $331,960
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10776891

## Citation

> US National Institutes of Health, RePORTER application 10776891, A molecular pathway that links N-glycosylation to birth defects (1R01HD113790-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10776891. Licensed CC0.

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