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

Yu Ri Lee, Se Hee Kim, Afif Ben-Mahmoud, Oc Hee Kim, Tae Ik Choi, Kang Han Lee, Bonsu Ku, Juneyong Eum, Yun Kee, Sangkyu Lee, Jihoon Cha, Dong Ju Won, Seung Tae Lee, Jong Rak Choi, Joon Soo Lee, Heung Dong Kim, Hyung Goo Kim, Joshua L. Bonkowsky, Hoon Chul Kang, Cheol Hee Kim

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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-A nd 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.

Original languageEnglish
Pages (from-to)331-342
Number of pages12
JournalHuman molecular genetics
Volume30
Issue number5
DOIs
Publication statusPublished - 2021 Mar 1

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: Journals.permissions@oup.com.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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