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Updated: Jan 8, 2026
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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
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Investigating and correcting a rare pathogenic mutation in GDF11
Sean T Congdon1, John Bennett1, Rhoddean Opinya1
1Biology Department, University of Hartford, West Hartford, CT, USA.
HGG Advances
|December 19, 2025
Summary
CRISPR prime editing successfully modeled and corrected a GDF11 gene mutation causing growth delay. This gene editing approach offers a new strategy for treating rare genetic disorders by precisely repairing pathogenic variants.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Biotechnology
Background:
- Single-nucleotide variants (SNVs) and indels cause most rare genetic disorders.
- Current therapeutic strategies for precise mutation correction are limited.
- Prime editing allows precise DNA repair without double-strand breaks.
Purpose of the Study:
- To model and correct a de novo GDF11 nonsense mutation (Tyr336*) using CRISPR prime editing.
- To investigate the cellular and molecular consequences of the GDF11 mutation.
- To establish a generalizable framework for disease modeling and gene correction.
Main Methods:
- Generated heterozygous GDF11 Tyr336* mutant HEK293T cells.
- Performed transcriptomic profiling to analyze gene expression changes.
- Applied and optimized CRISPR prime editing strategies (PE7) for mutation correction.
- Introduced a silent mutation to enhance editing efficiency and stability.
Main Results:
- GDF11 Tyr336* mutation led to reduced GDF11 protein levels and Golgi abnormalities.
- Transcriptomic analysis revealed dysregulation of metabolic, biosynthetic, cell-adhesion, and extracellular matrix genes.
- CRISPR prime editing, specifically PE7, effectively corrected the GDF11 mutation in human cells.
- Optimized prime editing strategy enhanced editing efficiency and stability.
Conclusions:
- The GDF11 Tyr336* allele acts via haploinsufficiency.
- CRISPR prime editing provides a viable method for modeling and correcting pathogenic variants.
- This study establishes a framework for allele-specific correction of genetic disorders.
