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The gene encoding isocitrate dehydrogenase 1 ( IDH1 ) is frequently mutated in several tumor types including gliomas. The most prevalent mutation in gliomas is a missense mutation leading to a substitution of arginine with histidine at the residue 132 (R132H). Wild type IDH1 catalyzes oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) whereas mutant IDH1 converts α-KG into D2-hydroxyglutarate (D2HG). Unfortunately, there are few  in vivo  model systems for  IDH -mutated tumors to study the effects of  IDH1  mutations in tumor development. We have therefore created transgenic zebrafish lines that express various  IDH1  mutants.    Materials and methods   IDH1  mutations ( IDH1   R132H  ,  IDH1   R132C   and loss-of-function mutation  IDH1   G70D  ),  IDH1   wildtype   or  eGFP  were cloned into constructs with several brain-specific promoters ( Nestin ,  Gfap  or  Gata2) . These constructs were injected into fertilized zebrafish eggs at the one-cell stage.    Results  In total more than ten transgenic zebrafish lines expressing various brain-specific  IDH1  mutations were created. A significant increase in the level of D2HG was observed in all transgenic lines expressing  IDH1   R132C   or  IDH1   R132H  , but not in any of the lines expressing  IDH1   wildtype  ,  IDH1   G70D   or  eGFP . No differences in 5-hydroxymethyl cytosine and mature collagen IV levels were observed between wildtype and mutant IDH1 transgenic fish. To our surprise, we failed to identify any strong phenotype, despite increased levels of the oncometabolite D2HG. No tumors were observed, even when backcrossing with  tp53 -mutant fish which suggests that additional transforming events are required for tumor formation. Elevated D2HG levels could be lowered by treatment of the transgenic zebrafish with an inhibitor of mutant IDH1 activity.    Conclusions  We have generated a transgenic zebrafish model system for mutations in  IDH1  that can be used for functional analysis and drug screening. Our model systems help understand the biology of  IDH1  mutations and its role in tumor formation.

IDH1-mutated transgenic zebrafish lines: An in-vivo model for drug screening and functional analysis