Vanishing white matter disease (VWMD) is an inherited leukodystrophy, causing CNS demyelination and high rates of morbidity and mortality. VWMD is autosomal recessive, and is caused by mutations in the five subunits of the eukaryotic translation initiation factor 2B (eIF2B) complex. eIF2B is the guanine nucleotide exchange factor for eIF2, and together they govern the rate of global protein synthesis. VWMD is characterized by reduced numbers of oligodendrocytes and astrocytes, as well as the progressive loss of myelinated axons. How mutations in eIF2B, a complex universally required for protein synthesis, disproportionately affects oligodendrocytes and astrocytes is not known. In yeast, null mutations in eIF2B(2-5) are non-viable which may indicate why in humans, mutations that prevent the expression of full-length EIF2B subunits have only been reported in the compound heterozygous state with a missense mutation as the second mutation. Because null mutations are most likely lethal in humans, this will limit the severity of phenotypes observed in individuals that survive to birth, making it difficult to determine the effects of EIF2B mutations in development. Importantly, mutations that severely compromise the function of eIF2B have not been studied in a vertebrate model system. The goal of our study is to develop a model of VWMD in zebrafish that recapitulates the clinical features of the disease, and to discover developmental defects associated with impaired function of eIF2B.
We have generated mutant alleles in the zebrafish eif2b subunits 2 and 5. Our characterization of these mutants has revealed a diversity of phenotypes that range in phenotypic severity from mild growth defects to early lethality. The eif2b5 alleles alter somatic growth rates in development, while only some alleles impact survival. To date, a point mutation in eif2b2 is the most severe allele characterized. eif2b2 mutants appear to develop normally, but by 5dpf are smaller in size compared to their siblings and display increased apoptosis in the fore-and-mid-brain, followed by early lethality by 10dpf. Our current study represents an essential step in the study of eIF2B related leukodystrophies, specifically by testing the function of several eif2b alleles in a vertebrate model organism. The genetic and developmental toolbox in the zebrafish field makes it a good candidate to develop disease models for the study of how developmental defects impact disease progression.