Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish
| Autor: | Cheol-Hee Kim, Seung-Tae Lee, Joon Soo Lee, Juneyong Eum, Hoon Chul Kang, Se Hee Kim, Bonsu Ku, Kang-Han Lee, Joshua L. Bonkowsky, Yun Kee, Tae-Ik Choi, Sangkyu Lee, Hyung-Goo Kim, Afif Ben-Mahmoud, Yu-Ri Lee, Oc-Hee Kim, Jihoon Cha, Heung Dong Kim, Dongju Won, Jong Rak Choi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular Vascular Endothelial Growth Factor A Protein Conformation Mutant Mutagenesis (molecular biology technique) Neovascularization Physiologic medicine.disease_cause 03 medical and health sciences Gene Knockout Techniques 0302 clinical medicine Leukoencephalopathies Stress Physiological Genetics medicine Animals Humans Clustered Regularly Interspaced Short Palindromic Repeats Molecular Biology Gene Zebrafish Genetics (clinical) Alleles Myelin Sheath Sequence Deletion Mutation biology Leukodystrophy Gene Expression Regulation Developmental Infant Cell Differentiation General Medicine biology.organism_classification medicine.disease Phenotype Glial cell differentiation Disease Models Animal Eukaryotic Initiation Factor-2B 030104 developmental biology Female 030217 neurology & neurosurgery |
| Zdroj: | Human molecular genetics. 30(5) |
| ISSN: | 1460-2083 |
| Popis: | Leukodystrophy with vanishing white matter (VWM), also called Childhood Ataxia with Central Nervous System Hypomyelination, 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 the 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. |
| Databáze: | OpenAIRE |
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