A Novel YWHAG Variant L173S Causes Developmental and Epileptic Encephalopathy by Disrupting the Hydrophobic Internal...

Developmental epileptic encephalopathy 56 (DEE56) is a monogenic DEE type caused by heterozygous mutations in YWHAG. To our knowledge, fewer than 30 cases of DEE56 have been reported globally, and our understanding of YWHAG's function remains limited.

Whole exome sequencing (WES) was performed on the patient and his parents. Structural conservation analysis of YWHAG was conducted using Consurf and PyMol. A literature search for relevant cases was performed in PubMed and Google Scholar.

The patient is a 6-year-2-month-old boy who developed refractory complex seizures starting at 8 months of age. He also exhibits intellectual disability, language impairment, and poor motor coordination. WES identified the de novo occurrence of a novel heterozygous YWHAG missense variant, c.518T>C (p.L173S), in the patient. L173 resides within the hydrophobic internal core formed by three alpha helices of YWHAG, and the residues constituting this internal core are highly evolutionarily conserved. The L173S substitution introduces a hydrophilic side chain into the hydrophobic core composed of three aliphatic residues. Ten missense mutations have been reported previously. Among them, five (E15, R57, D129, R132, and Y133) are associated with the ligand-binding region.

The functional domain involving the L173 residue of YWHAG remains unknown. Our findings suggest that the disruption of the stability of the highly conserved internal core of the YWHAG protein may be one mechanism leading to functional impairment, distinct from the previously proposed pathogenic models of dimer formation defects and/or impaired binding to phosphopeptide ligands. This may provide insights into the functional mechanisms of YWHAG and potential therapeutic strategies.