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Three additional patients with EED-associated overgrowth: potential mutation hotspots identified?
Catherine J Spellicy1, Yunhui Peng2, Leah Olewiler3
1Greenwood Genetic Center, Greenwood, SC, 29646, USA.
Journal of Human Genetics
|March 13, 2019
Summary
Genetic variants in the embryonic ectoderm development (EED) gene are linked to syndromic overgrowth. Specific EED protein regions act as mutation hotspots, affecting protein stability and interactions, potentially explaining overgrowth conditions.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Biology
Background:
- Syndromic overgrowth disorders share clinical features.
- The embryonic ectoderm development (EED) gene is implicated in these conditions.
Purpose of the Study:
- To report three new patients with missense variants in the EED gene.
- To investigate the functional impact of EED variants on protein structure and interactions.
Main Methods:
- Clinical case reporting.
- In silico modeling and free energy change calculations.
Main Results:
- Three new patients with missense EED variants were identified.
- All reported missense variants are in WD40 domains, crucial for EZH2 interaction.
- Pathogenic variants cluster at four specific amino acid residues, indicating mutation hotspots.
- In silico analyses suggest variants destabilize EED and impair EED-EZH2-H3K27me3 interactions.
Conclusions:
- Recurrent variants in EED's WD40 domain are associated with syndromic overgrowth.
- These variants likely cause overgrowth by disrupting EED protein function and its interaction network.
- Specific residues in the EED WD40 domain represent critical mutation hotspots.
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