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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  ;  DongJu 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 
 HUMAN MOLECULAR GENETICS, Vol.30(5) : 331-342, 2021-04 
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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.
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1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Se Hee(김세희) ORCID logo https://orcid.org/0000-0001-7773-1942
Kim, Heung Dong(김흥동) ORCID logo https://orcid.org/0000-0002-8031-7336
Won, Dongju(원동주) ORCID logo https://orcid.org/0000-0002-0084-0216
Lee, Seung-Tae(이승태) ORCID logo https://orcid.org/0000-0003-1047-1415
Lee, Joon Soo(이준수) ORCID logo https://orcid.org/0000-0001-9036-9343
Cha, Jihoon(차지훈)
Choi, Jong Rak(최종락) ORCID logo https://orcid.org/0000-0002-0608-2989
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