# O-glycosylation mechanisms of neurological deficits in congenital disorders of glycosylation

> **NIH NIH K08** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $180,760

## Abstract

PROJECT SUMMARY/ABSTRACT
Glycosylation is an essential, post-translational modification with complex and poorly understood roles in
protein function. My long-term objective is to elucidate the neurobiological functions of glycosylation, including
identifying the roles of critical glycosylation sites in neuronal protein function. The importance of glycosylation
is emphasized by the congenital disorders of glycosylation (CDG), a group of genetic disorders that disrupt
cellular glycosylation machinery. Affected patients exhibit severe neurological deficits. The genetic basis of
CDG provides an opportunity to identify the neurobiological functions of glycosylation using mouse models and
glycoproteomics. Understanding glycosylation in the nervous system will elucidate the pathophysiology of
CDGs and other neurological diseases, enable therapeutic advances targeting glycosylation pathways, and
inform normal function of glycosylation.
GALNT2-CDG is a new CDG type caused by biallelic mutations in GALNT2, which encodes a critical
glycosyltransferase initiating the first step in mucin-type O-glycosylation. GALNT2-CDG patients suffer from
epilepsy and global developmental delay. Galnt2 constitutional knock-out mice recapitulate many of the patient
neurological deficits. My central hypothesis is that site-specific loss of O-glycosylation on neural proteins
contributes to neurological dysfunction. The specific objective of this project is to identify the cause of
neurological dysfunction in GALNT2-CDG. This will be achieved by determining cellular origins of Galnt2
deficiency-mediated neurological deficits using Cre-mediated deletion of Galnt2 in neural cells and by
identifying disrupted O-glycosylation in these cells using glycoproteomics.
This proposed five-year career development plan focuses on achieving four objectives: develop research skills
in mouse models and glycoproteomics, increase my knowledgebase in neuroscience and glycobiology,
establish a body of work focusing on the role of glycosylation in the context of neurobiology, and obtain the
necessary skills to transition to independence. Mentoring will be provided by Dr. Zhaolan Zhou, a recognized
leader in the development and investigation of mouse models of genetic disorders that affect brain
development and function, and Dr. Benjamin Garcia, a recognized expert in developing quantitative mass
spectrometry techniques to interrogate post-translational modifications.
The skill set developed through these investigations and career development plan will make me uniquely
poised to uncover glycosylation-mediated mechanisms of CDG and other neurological diseases, as well as to
elucidate the critical roles of glycosylation in human neurological function. These studies will generate new
tools and a foundation to establish a long-term research program to investigate the pathophysiology of various
glycosylation-related disorders in the nervous system and prepare me to become an independent R01-funded
physic...

## Key facts

- **NIH application ID:** 10250486
- **Project number:** 5K08NS118119-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Andrew Charles Edmondson
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $180,760
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250486

## Citation

> US National Institutes of Health, RePORTER application 10250486, O-glycosylation mechanisms of neurological deficits in congenital disorders of glycosylation (5K08NS118119-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10250486. Licensed CC0.

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