YWHAG (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, gamma isoform), a member of the 14–3-3γ protein family, is involved in modulating cell survival and control of apoptosis. Inhibition of 14-3-3γ and ligand protein binding causes apoptosis. YWHAG plays an important role in signal transduction leading to mitosis and cellular proliferation. YWHAG was identified as a candidate gene for epilepsy by Komoike et al. (2010). Here, they reported two patients with Williams-Beuren Syndrome (WBS) who presented with infantile spasms, a rare presentation in WBS. Subsequent arrayCGH and FISH analysis identified atypical deletions of 7q11. In one patient, the deletion extended to the distal telomeric region, containing YWHAG, amongst other genes, suggesting haploinsufficiency of YWHAG as the likely explanation.
All the reported variants in YWHAG are missense substitutions except one truncating stop variant. Among those, there are two recurrent variants, p.R132C (five individuals), and p.Y133S (two individuals). Analysis on the effects of YWHAG missense mutations on protein–protein interaction binding affinity showed that mutation, p.R132C would have relatively stronger influence on 14-3-3γ binding affinity compared to other mutations, potentially being one of explanations for the severe phenotype. Previous study revealed that only the dimeric form of 14-3-3γ supports target proteins activity; and mutant 14-3-3γ with missense mutations would produce abnormal 14-3-3γ dimers, which consist of a wild-type 14-3-3γ monomer and a mutant monomer with impaired ability of binding to target proteins. Thus, a heterozygous missense mutation would lead to majority dimers being mutants, and the phenotype severity potentially depends on the damaging effect of the missense mutation. In contrast, a heterozygous truncating mutation would lead to only decreasing the number of wild-type dimer, due to the inability of mutants in forming dimers, explaining the mild phenotype associated with the heterozygous truncating mutation.
In vitro functional expression studies are not performed in the variants reported, but all the missense are predicted to impair dimerization and/or phosphopeptide binding. Guellla et al. (2017) noted that a decrease or increase in Ywhag in mice leads to delayed neuronal migration of pyramidal neurons in the developing brain and that atypical neuronal migration has been implicated in epilepsy.
Molecular diagnosis:
Mutations in YWHAG can be identified using molecular genetic testing, either by targeted sequencing of the YWHAG gene or exome/genome sequencing.
YWHAG