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

The zebrafish has become an appropriate animal model in the analysis of numerous human brain disorders. A variety of neuropsychiatric conditions and neurodevelopmental disorders are comorbid with abnormal social behavior. Given the translational relevance of zebrafish, multidisciplinary studies employing behavioral, neurobiological, and molecular methods with this species may provide insights into human central nervous system (CNS) disorders. Many of these studies impinge upon our ability to properly induce and quantify the behavior of zebrafish, a relatively understudied aspect of this species. In this study, we investigate how the body size of conspecifics relative to that of the test subject influences social (shoaling) responses in zebrafish. We found a robust preference by wild-type (WT) test zebrafish toward big conspecifics, but not toward smaller conspecifics. Additionally, we tested an autism-relevant zebrafish knockout (KO) model. The dyrk1aa KO zebrafish showed impaired social preference compared with WT in the social behavior test. Our results confirm the effect of relative body size on social preference and that the social preference task developed for zebrafish may uncover the function of genes and biological mechanisms potentially associated with human CNS disorders.

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