# REGULATION OF SKELETAL MUSCLE DEVELOPMENT AND MAINTENANCE BY PROTEIN O-GLUCOSYLTRANSFERASE 1 (POGLUT1)

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $385,724

## Abstract

SUMMARY
Carbohydrate addition (glycosylation) is one of the most common posttranslational modifications of
secreted and cell surface proteins. Glycosylation is critical for normal animal development and
physiology, and mutations in genes involved in glycosylation cause more than a 100 human diseases
with diverse phenotypes. However, glycan structures are complex, and each form of glycosylation
can be found in tens to thousands of target proteins. Accordingly, understanding the molecular
mechanisms underlying glycosylation disorders constitute a major challenge. One of the critical roles
played by protein glycosylation is the regulation of a cell-to-cell communication mechanism called the
Notch signaling pathway. Notch signaling regulates many processes during animal development and
adult maintenance. For example, studies in mice and cell culture have shown that muscle
development and muscle repair after injury depend on Notch signaling in mammals. However,
mutations in Notch pathway components or modulators have not been reported in human patients
with muscular dystrophy. We have recently reported a consanguineous family in which several
siblings suffer from LGMD-2Z, which is a new form of limb-girdle muscular dystrophy. LGMD-2Z is
caused by homozygosity for a recessive mutation in a gene called POGLUT1. POGLUT1 is a
glycosyltransferase which adds O-linked glucose to a number of transmembrane and secreted
proteins, including multiple components of the Notch signaling pathway. We have previously shown
that POGLUT1 regulates Notch signaling in fruit flies and mice. Analysis of the muscle tissues and
myoblasts isolated from the above-mentioned patients provided evidence suggesting that impaired
Notch signaling plays an important role in the pathophysiology of this form of muscular dystrophy.
However, the biologically-relevant targets of POGLUT1 in the Notch pathway and other pathways in
the muscle are not known. In this proposal, we will use biochemical and cell culture assays,
proteomic profiling, mouse genetic experiments and iPS cell experiments to determine the molecular
mechanisms underlying the regulation of muscle development and maintenance by POGLUT1 and to
identify its relevant targets. We will use iPS cells from patients, along with a CRISPR/Cas9-mediated
corrected version of them, for in vitro disease modeling and in vivo engraftment experiments. These
studies have the potential to provide novel insight into the pathophysiology of a muscular dystrophy
caused by abnormal glycosylation and might establish a new framework for future therapeutic
approaches for muscle diseases.

## Key facts

- **NIH application ID:** 10065324
- **Project number:** 1R01AR076770-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Radbod Darabi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,724
- **Award type:** 1
- **Project period:** 2020-07-08 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065324

## Citation

> US National Institutes of Health, RePORTER application 10065324, REGULATION OF SKELETAL MUSCLE DEVELOPMENT AND MAINTENANCE BY PROTEIN O-GLUCOSYLTRANSFERASE 1 (POGLUT1) (1R01AR076770-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065324. Licensed CC0.

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