Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish

Abstract Leukodystrophy with vanishing white matter (VWM), also called Childhood Ataxia Central Nervous System Hypomyelination, is caused by mutations in the subunits of eukaryotic translation initiation factor, EIF2B1, EIF2B2, EIF2B3, EIF2B4 or EIF2B5. However, little known regarding underlying pathogenetic mechanisms, and there no curative treatment for VWM. In this study, we established first EIF2B3 animal model VWM disease vertebrates CRISPR mutagenesis highly conserved zebrafish ortholog eif2b3. Using CRISPR, generated two mutant alleles eif2b3, 10- 16-bp deletions, respectively. The eif2b3 mutants showed defects myelin development glial cell differentiation, increased expression genes induced stress response pathway. Interestingly, found ectopic angiogenesis VEGF expression. Ectopic was reduced administration receptor inhibitor SU5416. together silico protein modeling analysis, demonstrated pathogenicity 18 reported as well a novel variant identified 19-month-old female patient: c.503 T > C (p.Leu168Pro). summary, our provides insights into pathogenesis offers rapid functional analysis human gene variants.